{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T06:54:24Z","timestamp":1773471264245,"version":"3.50.1"},"reference-count":139,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007382","name":"Universidade Federal Do Par\u00e1","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007382","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Comput Aided Mol Des"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The papain-like protease of SARS-CoV-2 (PLpro2) is integral to viral polyprotein cleavage and the modulation of host immune responses, positioning it as a critical target for antiviral drug development. Here, we elucidate the molecular mechanisms governing the noncovalent inhibition of PLpro2 through a comprehensive computational approach, including molecular docking, extensive molecular dynamics (MD) simulations, binding free energy calculations (MM\/GBSA and SIE), principal component and free energy landscape (PCA\/FEL) analyses, and protein\u2013ligand interaction fingerprinting (ProLIF). We assessed a structurally diverse set of noncovalent inhibitors for their capacity to induce conformational rearrangements and stabilize key structural motifs of PLpro2, with particular emphasis on the BL2 loop. Notably, XR3 and A19 exhibited superior experimental and predicted binding affinities, which can be attributed to favorable contacts with essential residues Tyr268 and Gln269, the attenuation of loop dynamics, and the stabilization of energetically favorable conformational states. By contrast, less potent inhibitors were associated with increased conformational heterogeneity, fragmented free energy landscapes, and diminished interactions with critical loop residues. Therefore, our integrative analysis delineates the structural and energetic determinants underpinning noncovalent PLpro2 inhibition, underscoring the central roles of loop immobilization and \u03c0-stacking interactions in the rational design of next-generation PLpro2 inhibitors.<\/jats:p>","DOI":"10.1007\/s10822-026-00763-z","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T02:28:43Z","timestamp":1770258523000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanistic insights into the noncovalent inhibition of SARS-CoV-2 PLpro: a multiscale computational study"],"prefix":"10.1007","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7772-8257","authenticated-orcid":false,"given":"Fl\u00e1vio Vin\u00edcius","family":"da Silva Ribeiro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6089-9260","authenticated-orcid":false,"given":"Renan Patrick","family":"da Penha Valente","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0606-2053","authenticated-orcid":false,"given":"Hendrik G.","family":"Kruger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4968-8005","authenticated-orcid":false,"given":"J\u00e9ssica","family":"de Oliveira Ara\u00fajo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2310-5107","authenticated-orcid":false,"given":"Jos\u00e9 Rog\u00e9rio A.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"763_CR1","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1080\/19397038.2021.1964634","volume":"14","author":"SS Priya","year":"2021","unstructured":"Priya SS, Cuce E, Sudhakar K (2021) A perspective of COVID 19 impact on global economy, energy and environment. Int J Sustain Eng 14:1290\u20131305","journal-title":"Int J Sustain Eng"},{"key":"763_CR2","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/s41562-021-01096-7","volume":"5","author":"A Josephson","year":"2021","unstructured":"Josephson A, Kilic T, Michler JD (2021) Socioeconomic impacts of COVID-19 in low-income countries. Nat Hum Behav 5:557\u2013565","journal-title":"Nat Hum Behav"},{"key":"763_CR3","doi-asserted-by":"publisher","first-page":"4848","DOI":"10.1016\/j.cell.2021.08.017","volume":"184","author":"EC Holmes","year":"2021","unstructured":"Holmes EC, Goldstein SA, Rasmussen AL, Robertson DL, Crits-Christoph A, Wertheim JO, Anthony SJ, Barclay WS, Boni MF, Doherty PC, Farrar J, Geoghegan JL, Jiang X, Leibowitz JL, Neil SJD, Skern T, Weiss SR, Worobey M, Andersen KG, Garry RF, Rambaut A (2021) The origins of SARS-CoV-2: a critical review. Cell 184:4848\u20134856","journal-title":"Cell"},{"key":"763_CR4","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.jare.2020.03.005","volume":"24","author":"MA Shereen","year":"2020","unstructured":"Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R (2020) COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. J Adv Res 24:91\u201398","journal-title":"J Adv Res"},{"key":"763_CR5","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.imj.2023.08.005","volume":"2","author":"MA Islam","year":"2023","unstructured":"Islam MA (2023) A review of SARS-CoV-2 variants and vaccines: viral properties, mutations, vaccine efficacy, and safety. Infect Med 2:247\u2013261","journal-title":"Infect Med"},{"key":"763_CR6","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/s41579-023-00878-2","volume":"21","author":"PV Markov","year":"2023","unstructured":"Markov PV, Ghafari M, Beer M, Lythgoe K, Simmonds P, Stilianakis NI, Katzourakis A (2023) The evolution of SARS-CoV-2. Nat Rev Microbiol 21:361\u2013379","journal-title":"Nat Rev Microbiol"},{"key":"763_CR7","doi-asserted-by":"publisher","DOI":"10.1002\/hsr2.70166","volume":"7","author":"M Erkihun","year":"2024","unstructured":"Erkihun M, Ayele B, Asmare Z, Endalamaw K (2024) Current updates on variants of SARS-CoV- 2: systematic review. Health Sci Rep 7:e70166","journal-title":"Health Sci Rep"},{"key":"763_CR8","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/jmv.25681","volume":"92","author":"Y Chen","year":"2020","unstructured":"Chen Y, Liu Q, Guo D (2020) Emerging coronaviruses: genome structure, replication, and pathogenesis. J Med Virol 92:418\u2013423","journal-title":"J Med Virol"},{"key":"763_CR9","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","volume":"395","author":"R Lu","year":"2020","unstructured":"Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W (2020) Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395:565\u2013574","journal-title":"Lancet"},{"key":"763_CR10","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","volume":"579","author":"F Wu","year":"2020","unstructured":"Wu F, Zhao S, Yu B, Chen Y-M, Wang W, Song Z-G, Hu Y, Tao Z-W, Tian J-H, Pei Y-Y, Yuan M-L, Zhang Y-L, Dai F-H, Liu Y, Wang Q-M, Zheng J-J, Xu L, Holmes EC, Zhang Y-Z (2020) A new coronavirus associated with human respiratory disease in China. Nature 579:265\u2013269","journal-title":"Nature"},{"key":"763_CR11","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","volume":"581","author":"J Shang","year":"2020","unstructured":"Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Geng Q, Auerbach A, Li F (2020) Structural basis of receptor recognition by SARS-CoV-2. Nature 581:221\u2013224","journal-title":"Nature"},{"key":"763_CR12","doi-asserted-by":"publisher","first-page":"10715","DOI":"10.1007\/s11033-022-07700-x","volume":"49","author":"SD Alipoor","year":"2022","unstructured":"Alipoor SD, Mirsaeidi M (2022) SARS-CoV-2 cell entry beyond the ACE2 receptor. Mol Biol Rep 49:10715\u201310727","journal-title":"Mol Biol Rep"},{"key":"763_CR13","doi-asserted-by":"crossref","unstructured":"R. Mukherjee and I. Dikic, in Encyclopedia of Cell Biology, Elsevier, 2023, pp. 930\u2013941.","DOI":"10.1016\/B978-0-12-821618-7.00111-5"},{"key":"763_CR14","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.antiviral.2014.12.015","volume":"115","author":"YM B\u00e1ez-Santos","year":"2015","unstructured":"B\u00e1ez-Santos YM, St John SE, Mesecar AD (2015) The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antivir Res 115:21\u201338","journal-title":"Antivir Res"},{"key":"763_CR15","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.151","volume":"3","author":"Q Hu","year":"2022","unstructured":"Hu Q, Xiong Y, Zhu G-H, Zhang Y-N, Zhang Y-W, Huang P, Ge G-B (2022) The SARS-CoV-2 main protease (Mpro): structure, function, and emerging therapies for COVID-19. MedComm 3:e151","journal-title":"MedComm"},{"key":"763_CR16","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.3390\/v2081803","volume":"2","author":"PCY Woo","year":"2010","unstructured":"Woo PCY, Huang Y, Lau SKP, Yuen K-Y (2010) Coronavirus genomics and bioinformatics analysis. Viruses 2:1804\u20131820","journal-title":"Viruses"},{"key":"763_CR17","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.antiviral.2017.11.001","volume":"149","author":"J Lei","year":"2018","unstructured":"Lei J, Kusov Y, Hilgenfeld R (2018) Nsp3 of coronaviruses: structures and functions of a large multi-domain protein. Antiviral Res 149:58\u201374","journal-title":"Antiviral Res"},{"key":"763_CR18","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1021\/acsptsci.0c00093","volume":"3","author":"BK Maiti","year":"2020","unstructured":"Maiti BK (2020) Can papain-like protease inhibitors halt SARS-CoV-2 replication? ACS Pharmacol Transl Sci 3:1017\u20131019","journal-title":"ACS Pharmacol Transl Sci"},{"key":"763_CR19","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.apsb.2020.08.014","volume":"11","author":"X Gao","year":"2021","unstructured":"Gao X, Qin B, Chen P, Zhu K, Hou P, Wojdyla JA, Wang M, Cui S (2021) Crystal structure of SARS-CoV-2 papain-like protease. Acta Pharm Sin B 11:237\u2013245","journal-title":"Acta Pharm Sin B"},{"key":"763_CR20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004113","volume":"10","author":"K Ratia","year":"2014","unstructured":"Ratia K, Kilianski A, Baez-Santos YM, Baker SC, Mesecar A (2014) Structural basis for the ubiquitin-linkage specificity and deISGylating activity of SARS-CoV papain-like protease. PLoS Pathog 10:e1004113","journal-title":"PLoS Pathog"},{"key":"763_CR21","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/s41579-018-0020-5","volume":"16","author":"Y-C Perng","year":"2018","unstructured":"Perng Y-C, Lenschow DJ (2018) ISG15 in antiviral immunity and beyond. Nat Rev Microbiol 16:423\u2013439","journal-title":"Nat Rev Microbiol"},{"key":"763_CR22","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","volume":"81","author":"D Komander","year":"2012","unstructured":"Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203\u2013229","journal-title":"Annu Rev Biochem"},{"key":"763_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21060-3","volume":"12","author":"J Osipiuk","year":"2021","unstructured":"Osipiuk J, Azizi S-A, Dvorkin S, Endres M, Jedrzejczak R, Jones KA, Kang S, Kathayat RS, Kim Y, Lisnyak VG, Maki SL, Nicolaescu V, Taylor CA, Tesar C, Zhang Y-A, Zhou Z, Randall G, Michalska K, Snyder SA, Dickinson BC, Joachimiak A (2021) Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat Commun 12:743","journal-title":"Nat Commun"},{"key":"763_CR24","doi-asserted-by":"publisher","DOI":"10.3390\/molecules30030491","author":"A Varghese","year":"2025","unstructured":"Varghese A, Liu J, Liu B, Guo W, Dong F, Patterson TA, Hong H (2025) Analysis of structures of SARS-CoV-2 papain-like protease bound with ligands unveils structural features for inhibiting the enzyme. Molecules. https:\/\/doi.org\/10.3390\/molecules30030491","journal-title":"Molecules"},{"key":"763_CR25","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/bs.enz.2021.09.004","volume":"50","author":"J Zephyr","year":"2021","unstructured":"Zephyr J, Yilmaz NK, Schiffer CA (2021) Viral proteases: structure, mechanism and inhibition. Enzymes 50:301\u2013333","journal-title":"Enzymes"},{"key":"763_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2022.101159","volume":"88","author":"T Majerov\u00e1","year":"2022","unstructured":"Majerov\u00e1 T, Konvalinka J (2022) Viral proteases as therapeutic targets. Mol Aspects Med 88:101159","journal-title":"Mol Aspects Med"},{"key":"763_CR27","doi-asserted-by":"publisher","first-page":"366","DOI":"10.3390\/v16030366","volume":"16","author":"PHO Borges","year":"2024","unstructured":"Borges PHO, Ferreira SB, Silva FP Jr (2024) Recent advances on targeting proteases for antiviral development. Viruses 16:366","journal-title":"Viruses"},{"key":"763_CR28","first-page":"95","volume":"7","author":"Z Lv","year":"2015","unstructured":"Lv Z, Chu Y, Wang Y (2015) HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV AIDS (Auckl) 7:95\u2013104","journal-title":"HIV AIDS (Auckl)"},{"key":"763_CR29","doi-asserted-by":"publisher","first-page":"3021","DOI":"10.1021\/jm201278q","volume":"55","author":"WM Kazmierski","year":"2012","unstructured":"Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji J-J, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang Y-K, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L (2012) Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants. J Med Chem 55:3021\u20133026","journal-title":"J Med Chem"},{"key":"763_CR30","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens13100825","volume":"13","author":"MA Diogo","year":"2024","unstructured":"Diogo MA, Cabral AGT, de Oliveira RB (2024) Advances in the search for SARS-CoV-2 Mpro and PLpro inhibitors. Pathogens 13:825","journal-title":"Pathogens"},{"key":"763_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2022.876212","volume":"10","author":"DJ Calleja","year":"2022","unstructured":"Calleja DJ, Lessene G, Komander D (2022) Inhibitors of SARS-CoV-2 PLpro. Front Chem 10:876212","journal-title":"Front Chem"},{"key":"763_CR32","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","volume":"383","author":"JH Beigel","year":"2020","unstructured":"Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, de Lopez Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh M-D, Ruiz-Palacios GM, Benfield T, F\u00e4tkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC, ACTT-1 Study Group Members (2020) Remdesivir for the treatment of Covid-19 - final report. N Engl J Med 383:1813\u20131826","journal-title":"N Engl J Med"},{"key":"763_CR33","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1126\/science.abl4784","volume":"374","author":"DR Owen","year":"2021","unstructured":"Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ, Dantonio A, Di L, Eng H, Ferre R, Gajiwala KS, Gibson SA, Greasley SE, Hurst BL, Kadar EP, Kalgutkar AS, Lee JC, Lee J, Liu W, Mason SW, Noell S, Novak JJ, Obach RS, Ogilvie K, Patel NC, Pettersson M, Rai DK, Reese MR, Sammons MF, Sathish JG, Singh RSP, Steppan CM, Stewart AE, Tuttle JB, Updyke L, Verhoest PR, Wei L, Yang Q, Zhu Y (2021) An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374:1586\u20131593","journal-title":"Science"},{"key":"763_CR34","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1056\/NEJMoa2116846","volume":"386","author":"RL Gottlieb","year":"2022","unstructured":"Gottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G, Oguchi G, Ryan P, Nielsen BU, Brown M, Hidalgo A, Sachdeva Y, Mittal S, Osiyemi O, Skarbinski J, Juneja K, Hyland RH, Osinusi A, Chen S, Camus G, Abdelghany M, Davies S, Behenna-Renton N, Duff F, Marty FM, Katz MJ, Ginde AA, Brown SM, Schiffer JT, Hill JA, GS-US-540-9012 (PINETREE) Investigators (2022) Early remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med 386:305\u2013315","journal-title":"N Engl J Med"},{"key":"763_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107379","volume":"147","author":"N Sakander","year":"2024","unstructured":"Sakander N, Ahmed A, Bhardwaj M, Kumari D, Nandi U, Mukherjee D (2024) A path from synthesis to emergency use authorization of molnupiravir as a COVID-19 therapy. Bioorg Chem 147:107379","journal-title":"Bioorg Chem"},{"key":"763_CR36","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1016\/j.drudis.2019.06.014","volume":"24","author":"V Parvathaneni","year":"2019","unstructured":"Parvathaneni V, Kulkarni NS, Muth A, Gupta V (2019) Drug repurposing: a promising tool to accelerate the drug discovery process. Drug Discov Today 24:2076\u20132085","journal-title":"Drug Discov Today"},{"key":"763_CR37","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.877813","volume":"13","author":"R Kulandaisamy","year":"2022","unstructured":"Kulandaisamy R, Kushwaha T, Dalal A, Kumar V, Singh D, Baswal K, Sharma P, Praneeth K, Jorwal P, Kayampeta SR, Sharma T, Maddur S, Kumar M, Kumar S, Polamarasetty A, Singh A, Sehgal D, Gholap SL, Appaiahgari MB, Katika MR, Inampudi KK (2022) Repurposing of FDA approved drugs against SARS-CoV-2 papain-like protease: computational, biochemical, and in vitro studies. Front Microbiol 13:877813","journal-title":"Front Microbiol"},{"key":"763_CR38","doi-asserted-by":"publisher","first-page":"16119","DOI":"10.1073\/pnas.0805240105","volume":"105","author":"K Ratia","year":"2008","unstructured":"Ratia K, Pegan S, Takayama J, Sleeman K, Coughlin M, Baliji S, Chaudhuri R, Fu W, Prabhakar BS, Johnson ME, Baker SC, Ghosh AK, Mesecar AD (2008) A noncovalent class of papain-like protease\/deubiquitinase inhibitors blocks SARS virus replication. Proc Natl Acad Sci U S A 105:16119\u201316124","journal-title":"Proc Natl Acad Sci U S A"},{"key":"763_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20718-8","volume":"12","author":"Z Fu","year":"2021","unstructured":"Fu Z, Huang B, Tang J, Liu S, Liu M, Ye Y, Liu Z, Xiong Y, Zhu W, Cao D, Li J, Niu X, Zhou H, Zhao YJ, Zhang G, Huang H (2021) The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery. Nat Commun 12:488","journal-title":"Nat Commun"},{"key":"763_CR40","doi-asserted-by":"crossref","unstructured":"T. Klemm, G. Ebert, D. J. Calleja, C. C. Allison, L. W. Richardson, J. P. Bernardini, B. G. Lu, N. W. Kuchel, C. Grohmann, Y. Shibata, Z. Y. Gan, J. P. Cooney, M. Doerflinger, A. E. Au, T. R. Blackmore, G. J. van der Heden van Noort, P. P. Geurink, H. Ovaa, J. Newman, A. Riboldi-Tunnicliffe, P. E. Czabotar, J. P. Mitchell, R. Feltham, B. C. Lechtenberg, K. N. Lowes, G. Dewson, M. Pellegrini, G. Lessene and D. Komander, Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2, EMBO J., 2020, 39, e106275.","DOI":"10.15252\/embj.2020106275"},{"key":"763_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-15181-y","volume":"12","author":"GM Ferreira","year":"2022","unstructured":"Ferreira GM, Pillaiyar T, Hirata MH, Poso A, Kronenberger T (2022) Inhibitor induced conformational changes in SARS-COV-2 papain-like protease. Sci Rep 12:11585","journal-title":"Sci Rep"},{"key":"763_CR42","doi-asserted-by":"publisher","first-page":"13384","DOI":"10.3390\/molecules200713384","volume":"20","author":"LG Ferreira","year":"2015","unstructured":"Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD (2015) Molecular docking and structure-based drug design strategies. Molecules 20:13384\u201313421","journal-title":"Molecules"},{"key":"763_CR43","doi-asserted-by":"publisher","first-page":"507","DOI":"10.2174\/1568026620666201207095626","volume":"21","author":"VB Sulimov","year":"2021","unstructured":"Sulimov VB, Kutov DC, Taschilova AS, Ilin IS, Tyrtyshnikov EE, Sulimov AV (2021) Docking paradigm in drug design. Curr Top Med Chem 21:507\u2013546","journal-title":"Curr Top Med Chem"},{"key":"763_CR44","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1146\/annurev-biochem-030222-120000","volume":"93","author":"JM Paggi","year":"2024","unstructured":"Paggi JM, Pandit A, Dror RO (2024) The art and science of molecular docking. Annu Rev Biochem 93:389\u2013410","journal-title":"Annu Rev Biochem"},{"key":"763_CR45","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","volume":"59","author":"M De Vivo","year":"2016","unstructured":"De Vivo M, Masetti M, Bottegoni G, Cavalli A (2016) Role of molecular dynamics and related methods in drug discovery. J Med Chem 59:4035\u20134061","journal-title":"J Med Chem"},{"key":"763_CR46","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1021\/cr300314q","volume":"114","author":"B Honarparvar","year":"2014","unstructured":"Honarparvar B, Govender T, Maguire GEM, Soliman MES, Kruger HG (2014) Integrated approach to structure-based enzymatic drug design: molecular modeling, spectroscopy, and experimental bioactivity. Chem Rev 114:493\u2013537","journal-title":"Chem Rev"},{"key":"763_CR47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113705","volume":"224","author":"VT Sabe","year":"2021","unstructured":"Sabe VT, Ntombela T, Jhamba LA, Maguire GEM, Govender T, Naicker T, Kruger HG (2021) Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: a review. Eur J Med Chem 224:113705","journal-title":"Eur J Med Chem"},{"key":"763_CR48","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1021\/acscentsci.1c00519","volume":"7","author":"C Ma","year":"2021","unstructured":"Ma C, Sacco MD, Xia Z, Lambrinidis G, Townsend JA, Hu Y, Meng X, Szeto T, Ba M, Zhang X, Gongora M, Zhang F, Marty MT, Xiang Y, Kolocouris A, Chen Y, Wang J (2021) Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and a FlipGFP-based reporter assay. ACS Cent Sci 7:1245\u20131260","journal-title":"ACS Cent Sci"},{"key":"763_CR49","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1016\/j.chembiol.2021.04.020","volume":"28","author":"H Shan","year":"2021","unstructured":"Shan H, Liu J, Shen J, Dai J, Xu G, Lu K, Han C, Wang Y, Xu X, Tong Y, Xiang H, Ai Z, Zhuang G, Hu J, Zhang Z, Li Y, Pan L, Tan L (2021) Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2. Cell Chem Biol 28:855-865.e9","journal-title":"Cell Chem Biol"},{"key":"763_CR50","doi-asserted-by":"publisher","first-page":"2940","DOI":"10.1021\/acs.jmedchem.1c01307","volume":"65","author":"Z Shen","year":"2022","unstructured":"Shen Z, Ratia K, Cooper L, Kong D, Lee H, Kwon Y, Li Y, Alqarni S, Huang F, Dubrovskyi O, Rong L, Thatcher GRJ, Xiong R (2022) Design of SARS-CoV-2 PLpro inhibitors for COVID-19 antiviral therapy leveraging binding cooperativity. J Med Chem 65:2940\u20132955","journal-title":"J Med Chem"},{"key":"763_CR51","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s13238-021-00836-9","volume":"12","author":"Y Zhao","year":"2021","unstructured":"Zhao Y, Du X, Duan Y, Pan X, Sun Y, You T, Han L, Jin Z, Shang W, Yu J, Guo H, Liu Q, Wu Y, Peng C, Wang J, Zhu C, Yang X, Yang K, Lei Y, Guddat LW, Xu W, Xiao G, Sun L, Zhang L, Rao Z, Yang H (2021) High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors. Protein Cell 12:877\u2013888","journal-title":"Protein Cell"},{"key":"763_CR52","doi-asserted-by":"publisher","first-page":"9904","DOI":"10.1039\/D0SC02646H","volume":"11","author":"K Sargsyan","year":"2020","unstructured":"Sargsyan K, Lin C-C, Chen T, Grauffel C, Chen Y-P, Yang W-Z, Yuan HS, Lim C (2020) Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors. Chem Sci 11:9904\u20139909","journal-title":"Chem Sci"},{"key":"763_CR53","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF chimera--a visualization system for exploratory research and analysis. J Comput Chem 25:1605\u20131612","journal-title":"J Comput Chem"},{"key":"763_CR54","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","volume":"267","author":"G Jones","year":"1997","unstructured":"Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727\u2013748","journal-title":"J Mol Biol"},{"key":"763_CR55","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1007\/s10822-012-9584-8","volume":"26","author":"M McGann","year":"2012","unstructured":"McGann M (2012) FRED and HYBRID docking performance on standardized datasets. J Comput Aided Mol Des 26:897\u2013906","journal-title":"J Comput Aided Mol Des"},{"key":"763_CR56","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","volume":"30","author":"GM Morris","year":"2009","unstructured":"Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785\u20132791","journal-title":"J Comput Chem"},{"key":"763_CR57","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","volume":"31","author":"O Trott","year":"2010","unstructured":"Trott O, Olson AJ (2010) Autodock vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455\u2013461","journal-title":"J Comput Chem"},{"key":"763_CR58","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1002\/jcc.23905","volume":"36","author":"WJ Allen","year":"2015","unstructured":"Allen WJ, Balius TE, Mukherjee S, Brozell SR, Moustakas DT, Lang PT, Case DA, Kuntz ID, Rizzo RC (2015) DOCK 6: impact of new features and current docking performance. J Comput Chem 36:1132\u20131156","journal-title":"J Comput Chem"},{"key":"763_CR59","doi-asserted-by":"crossref","unstructured":"G. Bitencourt-Ferreira and W. F. de Azevedo Jr, Molegro Virtual Docker for docking, Methods Mol. Biol., 2019, 2053, 149\u2013167","DOI":"10.1007\/978-1-4939-9752-7_10"},{"key":"763_CR60","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1021\/ci800298z","volume":"49","author":"O Korb","year":"2009","unstructured":"Korb O, St\u00fctzle T, Exner TE (2009) Empirical scoring functions for advanced protein-ligand docking with PLANTS. J Chem Inf Model 49:84\u201396","journal-title":"J Chem Inf Model"},{"key":"763_CR61","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1002\/bip.10207","volume":"68","author":"MR McGann","year":"2003","unstructured":"McGann MR, Almond HR, Nicholls A, Grant JA, Brown FK (2003) Gaussian docking functions. Biopolymers 68:76\u201390","journal-title":"Biopolymers"},{"key":"763_CR62","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1002\/jcc.20634","volume":"28","author":"R Huey","year":"2007","unstructured":"Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145\u20131152","journal-title":"J Comput Chem"},{"key":"763_CR63","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1002\/jcc.27218","volume":"45","author":"TE Balius","year":"2024","unstructured":"Balius TE, Tan YS, Chakrabarti M (2024) DOCK 6: incorporating hierarchical traversal through precomputed ligand conformations to enable large-scale docking. J Comput Chem 45:47\u201363","journal-title":"J Comput Chem"},{"key":"763_CR64","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.1021\/jm051197e","volume":"49","author":"R Thomsen","year":"2006","unstructured":"Thomsen R, Christensen MH (2006) Moldock: a new technique for high-accuracy molecular docking. J Med Chem 49:3315\u20133321","journal-title":"J Med Chem"},{"key":"763_CR65","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1021\/ci010025x","volume":"41","author":"R Wang","year":"2001","unstructured":"Wang R, Wang S (2001) How does consensus scoring work for virtual library screening? An idealized computer experiment. J Chem Inf Comput Sci 41:1422\u20131426","journal-title":"J Chem Inf Comput Sci"},{"key":"763_CR66","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2020.107735","volume":"101","author":"MD de Oliveira","year":"2020","unstructured":"de Oliveira MD, de O. Ara\u00fajo J, Gal\u00facio JMP, Santana K, Lima AH (2020) Targeting shikimate pathway: in silico analysis of phosphoenolpyruvate derivatives as inhibitors of EPSP synthase and DAHP synthase. J Mol Graph Model 101:107735","journal-title":"J Mol Graph Model"},{"key":"763_CR67","doi-asserted-by":"publisher","first-page":"35383","DOI":"10.1039\/D1RA05785E","volume":"11","author":"V Scardino","year":"2021","unstructured":"Scardino V, Bollini M, Cavasotto CN (2021) Combination of pose and rank consensus in docking-based virtual screening: the best of both worlds. RSC Adv 11:35383\u201335391","journal-title":"RSC Adv"},{"key":"763_CR68","doi-asserted-by":"publisher","first-page":"2980","DOI":"10.1021\/ci500424n","volume":"54","author":"T Tuccinardi","year":"2014","unstructured":"Tuccinardi T, Poli G, Romboli V, Giordano A, Martinelli A (2014) Extensive consensus docking evaluation for ligand pose prediction and virtual screening studies. J Chem Inf Model 54:2980\u20132986","journal-title":"J Chem Inf Model"},{"key":"763_CR69","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1021\/acs.jcim.8b00329","volume":"58","author":"X Ren","year":"2018","unstructured":"Ren X, Shi Y-S, Zhang Y, Liu B, Zhang L-H, Peng Y-B, Zeng R (2018) Novel consensus docking strategy to improve ligand pose prediction. J Chem Inf Model 58:1662\u20131668","journal-title":"J Chem Inf Model"},{"key":"763_CR70","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1021\/ci0503255","volume":"46","author":"H Chen","year":"2006","unstructured":"Chen H, Lyne PD, Giordanetto F, Lovell T, Li J (2006) On evaluating molecular-docking methods for pose prediction and enrichment factors. J Chem Inf Model 46:401\u2013415","journal-title":"J Chem Inf Model"},{"key":"763_CR71","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.1021\/ci200227u","volume":"51","author":"RA Laskowski","year":"2011","unstructured":"Laskowski RA, Swindells MB (2011) LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51:2778\u20132786","journal-title":"J Chem Inf Model"},{"key":"763_CR72","volume-title":"Amber 2022","author":"DA Case","year":"2022","unstructured":"Case DA, Aktulga HM, Belfon K, Ben-Shalom IY, Berryman JT, Brozell SR, Cerutti DS, Cheatham TE III, Cisneros GA, Cruzeiro VWD, Darden TA, Duke RE, Giambasu G, Gilson MK, Gohlke H, Goetz AW, Harris R, Izadi S, Izmailov SA, Kasavajhala K, Kaymak MC, King E, Kovalenko A, Kurtzman T, Lee TS, LeGrand S, Li P, Lin C, Liu J, Luchko T, Luo R, Machado M, Man V, Manathunga M, Merz KM, Miao Y, Mikhailovskii O, Monard G, Nguyen H, O\u2019Hearn KA, Onufriev A, Pan F, Pantano S, Qi R, Rahnamoun A, Roe DR, Roitberg A, Sagui C, Schott-Verdugo S, Shajan A, Shen J, Simmerling CL, Skrynnikov NR, Smith J, Swails J, Walker RC, Wang J, Wang J, Wei H, Wolf RM, Wu X, Xiong Y, Xue Y, York DM, Zhao S, Kollman PA (2022) Amber 2022. University of California, San Francisco"},{"key":"763_CR73","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1002\/jcc.25187","volume":"39","author":"DJ Mermelstein","year":"2018","unstructured":"Mermelstein DJ, Lin C, Nelson G, Kretsch R, McCammon JA, Walker RC (2018) Fast and flexible gpu accelerated binding free energy calculations within the amber molecular dynamics package. J Comput Chem 39:1354\u20131358","journal-title":"J Comput Chem"},{"key":"763_CR74","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/BF00533485","volume":"28","author":"PC Hariharan","year":"1973","unstructured":"Hariharan PC, Pople JA (1973) The influence of polarization functions on molecular orbital hydrogenation energies. Theor Chem Acc 28:213\u2013222","journal-title":"Theor Chem Acc"},{"key":"763_CR75","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1002\/1096-987X(200009)21:12<1049::AID-JCC3>3.0.CO;2-F","volume":"21","author":"J Wang","year":"2000","unstructured":"Wang J, Cieplak P, Kollman PA (2000) How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J Comput Chem 21:1049\u20131074","journal-title":"J Comput Chem"},{"key":"763_CR76","unstructured":"Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich A, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB and Fox DJ, Gaussian 09, Revision E.01, Gaussian, Inc., Wallingford CT, 2016."},{"key":"763_CR77","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1021\/ct100578z","volume":"7","author":"MHM Olsson","year":"2011","unstructured":"Olsson MHM, S\u00f8ndergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: Consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput 7:525\u2013537","journal-title":"J Chem Theory Comput"},{"key":"763_CR78","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","volume":"25","author":"J Wang","year":"2004","unstructured":"Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157\u20131174","journal-title":"J Comput Chem"},{"key":"763_CR79","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1021\/acs.jctc.9b00591","volume":"16","author":"C Tian","year":"2020","unstructured":"Tian C, Kasavajhala K, Belfon KAA, Raguette L, Huang H, Migues AN, Bickel J, Wang Y, Pincay J, Wu Q, Simmerling C (2020) Ff19SB: amino-acid-specific protein backbone parameters trained against quantum mechanics energy surfaces in solution. J Chem Theory Comput 16:528\u2013552","journal-title":"J Chem Theory Comput"},{"key":"763_CR80","doi-asserted-by":"publisher","first-page":"2935","DOI":"10.1021\/ct1002626","volume":"6","author":"MB Peters","year":"2010","unstructured":"Peters MB, Yang Y, Wang B, F\u00fcsti-Moln\u00e1r L, Weaver MN, Merz KM (2010) Structural survey of zinc-containing proteins and development of the zinc AMBER force field (ZAFF). J Chem Theory Comput 6:2935\u20132947","journal-title":"J Chem Theory Comput"},{"key":"763_CR81","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","volume":"79","author":"WL Jorgensen","year":"1983","unstructured":"Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926\u2013935","journal-title":"J Chem Phys"},{"key":"763_CR82","doi-asserted-by":"publisher","first-page":"6183","DOI":"10.1021\/acs.jcim.3c01153","volume":"63","author":"DA Case","year":"2023","unstructured":"Case DA, Aktulga HM, Belfon K, Cerutti DS, Cisneros GA, Cruzeiro VWD, Forouzesh N, Giese TJ, G\u00f6tz AW, Gohlke H, Izadi S, Kasavajhala K, Kaymak MC, King E, Kurtzman T, Lee T-S, Li P, Liu J, Luchko T, Luo R, Manathunga M, Machado MR, Nguyen HM, O\u2019Hearn KA, Onufriev AV, Pan F, Pantano S, Qi R, Rahnamoun A, Risheh A, Schott-Verdugo S, Shajan A, Swails J, Wang J, Wei H, Wu X, Wu Y, Zhang S, Zhao S, Zhu Q, Cheatham TE 3rd, Roe DR, Roitberg A, Simmerling C, York DM, Nagan MC, Merz KM Jr (2023) AmberTools. J Chem Inf Model 63:6183\u20136191","journal-title":"J Chem Inf Model"},{"key":"763_CR83","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1002\/bip.360320508","volume":"32","author":"RJ Loncharich","year":"1992","unstructured":"Loncharich RJ, Brooks BR, Pastor RW (1992) Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N\u2019-methylamide. Biopolymers 32:523\u2013535","journal-title":"Biopolymers"},{"key":"763_CR84","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","volume":"98","author":"T Darden","year":"1993","unstructured":"Darden T, York D, Pedersen L (1993) Particle mesh Ewald: An N \u22c5log( N ) method for Ewald sums in large systems. J Chem Phys 98:10089\u201310092","journal-title":"J Chem Phys"},{"key":"763_CR85","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","volume":"23","author":"J-P Ryckaert","year":"1977","unstructured":"Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327\u2013341","journal-title":"J Comput Phys"},{"key":"763_CR86","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1103\/PhysRev.165.201","volume":"165","author":"L Verlet","year":"1968","unstructured":"Verlet L (1968) Computer \u201cexperiments\u201d on classical fluids. II. Equilibrium correlation functions. Phys Rev 165:201\u2013214","journal-title":"Phys Rev"},{"key":"763_CR87","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1021\/ct400341p","volume":"9","author":"DR Roe","year":"2013","unstructured":"Roe DR, Cheatham TE 3rd (2013) PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput 9:3084\u20133095","journal-title":"J Chem Theory Comput"},{"key":"763_CR88","doi-asserted-by":"publisher","DOI":"10.1063\/1.4922925","volume":"142","author":"M Grosso","year":"2015","unstructured":"Grosso M, Kalstein A, Parisi G, Roitberg AE, Fernandez-Alberti S (2015) On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein. J Chem Phys 142:245101","journal-title":"J Chem Phys"},{"key":"763_CR89","doi-asserted-by":"publisher","DOI":"10.1002\/cphc.202200491","volume":"24","author":"J Palma","year":"2023","unstructured":"Palma J, Pierdominici-Sottile G (2023) On the uses of PCA to characterise molecular dynamics simulations of biological macromolecules: basics and tips for an effective use. ChemPhysChem 24:e202200491","journal-title":"ChemPhysChem"},{"key":"763_CR90","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/978-1-62703-658-0_11","volume":"1084","author":"CC David","year":"2014","unstructured":"David CC, Jacobs DJ (2014) Principal component analysis: a method for determining the essential dynamics of proteins. Methods Mol Biol 1084:193\u2013226","journal-title":"Methods Mol Biol"},{"key":"763_CR91","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/S0065-3233(03)66004-3","volume":"66","author":"BO Brandsdal","year":"2003","unstructured":"Brandsdal BO, \u00d6sterberg F, Alml\u00f6f M, Feierberg I, Luzhkov VB, \u00c5qvist J (2003) Free energy calculations and ligand binding.\". Adv Protein Chem 66:123\u2013158","journal-title":"Adv Protein Chem"},{"key":"763_CR92","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1126\/science.1077809","volume":"298","author":"MM Garcia-Mira","year":"2002","unstructured":"Garcia-Mira MM, Sadqi M, Fischer N, Sanchez-Ruiz JM, Mu\u00f1oz V (2002) Experimental identification of downhill protein folding. Science 298:2191\u20132195","journal-title":"Science"},{"key":"763_CR93","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/prot.340210302","volume":"21","author":"JD Bryngelson","year":"1995","unstructured":"Bryngelson JD, Onuchic JN, Socci ND, Wolynes PG (1995) Funnels, pathways, and the energy landscape of protein folding: a synthesis. Proteins 21:167\u2013195","journal-title":"Proteins"},{"key":"763_CR94","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/j.jmgm.2009.01.006","volume":"27","author":"E Papaleo","year":"2009","unstructured":"Papaleo E, Mereghetti P, Fantucci P, Grandori R, De Gioia L (2009) Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: the myoglobin case. J Mol Graph Model 27:889\u2013899","journal-title":"J Mol Graph Model"},{"key":"763_CR95","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1021\/ar000033j","volume":"33","author":"PA Kollman","year":"2000","unstructured":"Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE 3rd (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889\u2013897","journal-title":"Acc Chem Res"},{"key":"763_CR96","doi-asserted-by":"publisher","first-page":"9478","DOI":"10.1021\/acs.chemrev.9b00055","volume":"119","author":"E Wang","year":"2019","unstructured":"Wang E, Sun H, Wang J, Wang Z, Liu H, Zhang JZH, Hou T (2019) End-point binding free energy calculation with MM\/PBSA and MM\/GBSA: strategies and applications in drug design. Chem Rev 119:9478\u20139508","journal-title":"Chem Rev"},{"key":"763_CR97","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1021\/ci600406v","volume":"47","author":"M Na\u00efm","year":"2007","unstructured":"Na\u00efm M, Bhat S, Rankin KN, Dennis S, Chowdhury SF, Siddiqi I, Drabik P, Sulea T, Bayly CI, Jakalian A, Purisima EO (2007) Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 1. Exploring the parameter space. J Chem Inf Model 47:122\u2013133","journal-title":"J Chem Inf Model"},{"key":"763_CR98","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1021\/ci2000242","volume":"51","author":"T Sulea","year":"2011","unstructured":"Sulea T, Cui Q, Purisima EO (2011) Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 2. Benchmark in the CSAR-2010 scoring exercise. J Chem Inf Model 51:2066\u20132081","journal-title":"J Chem Inf Model"},{"key":"763_CR99","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1210576","volume":"10","author":"EO Purisima","year":"2023","unstructured":"Purisima EO, Corbeil CR, Gaudreault F, Wei W, Deprez C, Sulea T (2023) Solvated interaction energy: from small-molecule to antibody drug design. Front Mol Biosci 10:1210576","journal-title":"Front Mol Biosci"},{"key":"763_CR100","doi-asserted-by":"publisher","first-page":"3314","DOI":"10.1021\/ct300418h","volume":"8","author":"BR Miller 3rd","year":"2012","unstructured":"Miller BR 3rd, McGee TD Jr, Swails JM, Homeyer N, Gohlke H, Roitberg AE (2012) MMPBSA.Py: an efficient program for end-state free energy calculations. J Chem Theory Comput 8:3314\u20133321","journal-title":"J Chem Theory Comput"},{"key":"763_CR101","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1021\/jm030331x","volume":"47","author":"Z Deng","year":"2004","unstructured":"Deng Z, Chuaqui C, Singh J (2004) Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions. J Med Chem 47:337\u2013344","journal-title":"J Med Chem"},{"key":"763_CR102","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-021-00548-6","volume":"13","author":"C Bouysset","year":"2021","unstructured":"Bouysset C, Fiorucci S (2021) ProLIF: a library to encode molecular interactions as fingerprints. J Cheminform 13:72","journal-title":"J Cheminform"},{"key":"763_CR103","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s10534-022-00373-w","volume":"35","author":"MW Thompson","year":"2022","unstructured":"Thompson MW (2022) Regulation of zinc-dependent enzymes by metal carrier proteins. Biometals 35:187\u2013213","journal-title":"Biometals"},{"key":"763_CR104","doi-asserted-by":"publisher","first-page":"7561","DOI":"10.1021\/acs.jmedchem.2c00303","volume":"65","author":"H Tan","year":"2022","unstructured":"Tan H, Hu Y, Jadhav P, Tan B, Wang J (2022) Progress and challenges in targeting the SARS-CoV-2 papain-like protease. J Med Chem 65:7561\u20137580","journal-title":"J Med Chem"},{"key":"763_CR105","doi-asserted-by":"publisher","first-page":"4681","DOI":"10.1039\/D3SC00166K","volume":"14","author":"Q Shao","year":"2023","unstructured":"Shao Q, Xiong M, Li J, Hu H, Su H, Xu Y (2023) Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches. Chem Sci 14:4681\u20134696","journal-title":"Chem Sci"},{"key":"763_CR106","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1111\/j.1747-0285.2007.00571.x","volume":"70","author":"OABSM Gani","year":"2007","unstructured":"Gani OABSM (2007) Signposts of docking and scoring in drug design. Chem Biol Drug Des 70:360\u2013365","journal-title":"Chem Biol Drug Des"},{"key":"763_CR107","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1038\/nrd1549","volume":"3","author":"DB Kitchen","year":"2004","unstructured":"Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 3:935\u2013949","journal-title":"Nat Rev Drug Discov"},{"key":"763_CR108","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.str.2009.02.010","volume":"17","author":"DL Mobley","year":"2009","unstructured":"Mobley DL, Dill KA (2009) Binding of small-molecule ligands to proteins: \u201cwhat you see\u201d is not always \u201cwhat you get,.\u201d Structure 17:489\u2013498","journal-title":"Structure"},{"key":"763_CR109","doi-asserted-by":"publisher","first-page":"4953","DOI":"10.1021\/jm00026a001","volume":"38","author":"MA Murcko","year":"1995","unstructured":"Murcko MA (1995) Computational methods to predict binding free energy in ligand-receptor complexes. J Med Chem 38:4953\u20134967","journal-title":"J Med Chem"},{"key":"763_CR110","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1063\/1.1749657","volume":"3","author":"JG Kirkwood","year":"1935","unstructured":"Kirkwood JG (1935) Statistical mechanics of fluid mixtures. J Chem Phys 3:300\u2013313","journal-title":"J Chem Phys"},{"key":"763_CR111","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1063\/1.1740409","volume":"22","author":"RW Zwanzig","year":"1954","unstructured":"Zwanzig RW (1954) High\u2010Temperature equation of state by a perturbation method. I. Nonpolar gases. J Chem Phys 22:1420\u20131426","journal-title":"J Chem Phys"},{"key":"763_CR112","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1007\/s10822-007-9159-2","volume":"22","author":"RE Amaro","year":"2008","unstructured":"Amaro RE, Baron R, McCammon JA (2008) An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J Comput Aided Mol Des 22:693\u2013705","journal-title":"J Comput Aided Mol Des"},{"key":"763_CR113","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.cbpa.2011.05.021","volume":"15","author":"A de Ruiter","year":"2011","unstructured":"de Ruiter A, Oostenbrink C (2011) Free energy calculations of protein-ligand interactions. Curr Opin Chem Biol 15:547\u2013552","journal-title":"Curr Opin Chem Biol"},{"key":"763_CR114","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1002\/jcc.21450","volume":"31","author":"CD Christ","year":"2010","unstructured":"Christ CD, Mark AE, Van Gunsteren WF (2010) Basic ingredients of free energy calculations: a review. J Comput Chem 31:1569\u20131582","journal-title":"J Comput Chem"},{"key":"763_CR115","doi-asserted-by":"publisher","first-page":"2632","DOI":"10.1021\/ct500161f","volume":"10","author":"N Hansen","year":"2014","unstructured":"Hansen N, van Gunsteren WF (2014) Practical aspects of free-energy calculations: a review. J Chem Theory Comput 10:2632\u20132647","journal-title":"J Chem Theory Comput"},{"key":"763_CR116","doi-asserted-by":"publisher","first-page":"3277","DOI":"10.1021\/acs.jcim.0c00179","volume":"60","author":"J Wang","year":"2020","unstructured":"Wang J (2020) Fast identification of possible drug treatment of Coronavirus Disease-19 (COVID-19) through computational drug repurposing study. J Chem Inf Model 60:3277\u20133286","journal-title":"J Chem Inf Model"},{"issue":"10","key":"763_CR117","doi-asserted-by":"publisher","first-page":"3662","DOI":"10.1080\/07391102.2020.1768151","volume":"39","author":"L Mittal","year":"2020","unstructured":"Mittal L, Kumari A, Srivastava M, Singh M, Asthana S (2020) Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach. J Biomol Struct Dyn 39(10):3662\u20133680","journal-title":"J Biomol Struct Dyn"},{"key":"763_CR118","doi-asserted-by":"publisher","first-page":"2904","DOI":"10.1080\/07391102.2020.1757510","volume":"39","author":"S Pant","year":"2021","unstructured":"Pant S, Singh M, Ravichandiran V, Murty USN, Srivastava HK (2021) Peptide-like and small-molecule inhibitors against Covid-19. J Biomol Struct Dyn 39:2904\u20132913","journal-title":"J Biomol Struct Dyn"},{"key":"763_CR119","doi-asserted-by":"publisher","first-page":"4425","DOI":"10.1021\/acs.jcim.1c00560","volume":"61","author":"B Jawad","year":"2021","unstructured":"Jawad B, Adhikari P, Podgornik R, Ching W-Y (2021) Key interacting residues between rbd of SARS-CoV-2 and ACE2 receptor: combination of molecular dynamics simulation and density functional calculation. J Chem Inf Model 61:4425\u20134441","journal-title":"J Chem Inf Model"},{"key":"763_CR120","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1007\/s10930-020-09945-6","volume":"40","author":"MAA Ibrahim","year":"2021","unstructured":"Ibrahim MAA, Abdelrahman AHM, Allemailem KS, Almatroudi A, Moustafa MF, Hegazy M-EF (2021) In silico evaluation of prospective anti-COVID-19 drug candidates as potential SARS-CoV-2 main protease inhibitors. Protein J 40:296\u2013309","journal-title":"Protein J"},{"key":"763_CR121","doi-asserted-by":"publisher","first-page":"23450","DOI":"10.1039\/D1RA03956C","volume":"11","author":"JRA Silva","year":"2021","unstructured":"Silva JRA, Kruger HG, Molfetta FA (2021) Drug repurposing and computational modeling for discovery of inhibitors of the main protease (Mpro) of SARS-CoV-2. RSC Adv 11:23450\u201323458","journal-title":"RSC Adv"},{"key":"763_CR122","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213972","volume":"23","author":"AM Balieiro","year":"2022","unstructured":"Balieiro AM, Anuncia\u00e7\u00e3o ELS, Costa CHS, Qayed WS, Silva JRA (2022) Computational analysis of SAM analogs as methyltransferase inhibitors of nsp16\/nsp10 complex from SARS-CoV-2. Int J Mol Sci 23:13972","journal-title":"Int J Mol Sci"},{"key":"763_CR123","doi-asserted-by":"publisher","unstructured":". da Costa CHS, de Freitas CAB, Dos Santos AM, da Silva de Souza CG, Silva JRA, Lameira J, Moliner V and Skaf MS, Conformational dynamics and binding interactions of SARS-CoV-2 spike protein variants: Omicron, XBB.1.9.2, and EG.5, J Chem Inf Model, https:\/\/doi.org\/10.1021\/acs.jcim.5c00308","DOI":"10.1021\/acs.jcim.5c00308"},{"key":"763_CR124","doi-asserted-by":"publisher","first-page":"13644","DOI":"10.1021\/acs.jpcb.1c07060","volume":"125","author":"K Sanachai","year":"2021","unstructured":"Sanachai K, Mahalapbutr P, Sanghiran Lee V, Rungrotmongkol T, Hannongbua S (2021) In silico elucidation of potent inhibitors and rational drug design against SARS-CoV-2 papain-like protease. J Phys Chem B 125:13644\u201313656","journal-title":"J Phys Chem B"},{"key":"763_CR125","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1021\/ci100275a","volume":"51","author":"T Hou","year":"2011","unstructured":"Hou T, Wang J, Li Y, Wang W (2011) Assessing the performance of the MM\/PBSA and MM\/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J Chem Inf Model 51:69\u201382","journal-title":"J Chem Inf Model"},{"key":"763_CR126","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.jmgm.2013.09.005","volume":"46","author":"C Mulakala","year":"2013","unstructured":"Mulakala C, Viswanadhan VN (2013) Could MM-GBSA be accurate enough for calculation of absolute protein\/ligand binding free energies? J Mol Graph Model 46:41\u201351","journal-title":"J Mol Graph Model"},{"key":"763_CR127","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1002\/jcc.21372","volume":"31","author":"G Rastelli","year":"2010","unstructured":"Rastelli G, Del Rio A, Degliesposti G, Sgobba M (2010) Fast and accurate predictions of binding free energies using MM-PBSA and MM-GBSA. J Comput Chem 31:797\u2013810","journal-title":"J Comput Chem"},{"key":"763_CR128","doi-asserted-by":"publisher","first-page":"4357","DOI":"10.1021\/acsomega.8b00123","volume":"3","author":"F Fratev","year":"2018","unstructured":"Fratev F, Steinbrecher T, J\u00f3nsd\u00f3ttir S\u00d3 (2018) Prediction of accurate binding modes using combination of classical and accelerated molecular dynamics and free-energy perturbation calculations: an application to toxicity studies. ACS Omega 3:4357\u20134371","journal-title":"ACS Omega"},{"key":"763_CR129","doi-asserted-by":"publisher","first-page":"3991","DOI":"10.1021\/jm040787u","volume":"47","author":"A Cavalli","year":"2004","unstructured":"Cavalli A, Bottegoni G, Raco C, De Vivo M, Recanatini M (2004) A computational study of the binding of propidium to the peripheral anionic site of human acetylcholinesterase. J Med Chem 47:3991\u20133999","journal-title":"J Med Chem"},{"key":"763_CR130","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","volume":"10","author":"S Genheden","year":"2015","unstructured":"Genheden S, Ryde U (2015) The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov 10:449\u2013461","journal-title":"Expert Opin Drug Discov"},{"key":"763_CR131","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1007\/s10822-010-9363-3","volume":"24","author":"J Michel","year":"2010","unstructured":"Michel J, Essex JW (2010) Prediction of protein-ligand binding affinity by free energy simulations: assumptions, pitfalls and expectations. J Comput Aided Mol Des 24:639\u2013658","journal-title":"J Comput Aided Mol Des"},{"key":"763_CR132","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1006\/jmbi.1994.1430","volume":"240","author":"AE Mark","year":"1994","unstructured":"Mark AE, van Gunsteren WF (1994) Decomposition of the free energy of a system in terms of specific interactions. Implications for theoretical and experimental studies. J Mol Biol 240:167\u2013176","journal-title":"J Mol Biol"},{"key":"763_CR133","doi-asserted-by":"publisher","first-page":"13735","DOI":"10.1021\/j100102a046","volume":"98","author":"PE Smith","year":"1994","unstructured":"Smith PE, van Gunsteren WF (1994) When are free energy components meaningful? J Phys Chem 98:13735\u201313740","journal-title":"J Phys Chem"},{"key":"763_CR134","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2022.105884","volume":"126","author":"WS Qayed","year":"2022","unstructured":"Qayed WS, Hassan MA, El-Sayed WM, Rog\u00e9rio A Silva J, Aboul-Fadl T (2022) Novel azine linked hybrids of 2-indolinone and thiazolodinone scaffolds as CDK2 inhibitors with potential anticancer activity: In silico design, synthesis, biological, molecular dynamics and binding free energy studies. Bioorg Chem 126:105884","journal-title":"Bioorg Chem"},{"key":"763_CR135","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1039\/D2RA06246A","volume":"13","author":"LS Martins","year":"2022","unstructured":"Martins LS, Kruger HG, Naicker T, Alves CN, Lameira J, Ara\u00fajo Silva JR (2022) Computational insights for predicting the binding and selectivity of peptidomimetic plasmepsin IV inhibitors against cathepsin D. RSC Adv 13:602\u2013614","journal-title":"RSC Adv"},{"key":"763_CR136","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1002\/prot.21395","volume":"67","author":"V Zoete","year":"2007","unstructured":"Zoete V, Michielin O (2007) Comparison between computational alanine scanning and per-residue binding free energy decomposition for protein-protein association using MM-GBSA: application to the TCR-p-MHC complex. Proteins 67:1026\u20131047","journal-title":"Proteins"},{"key":"763_CR137","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.ijbiomac.2018.07.050","volume":"119","author":"A Gupta","year":"2018","unstructured":"Gupta A, Chaudhary N, Aparoy P (2018) MM-PBSA and per-residue decomposition energy studies on 7-phenyl-imidazoquinolin-4(5H)-one derivatives: identification of crucial site points at microsomal prostaglandin E synthase-1 (mPGES-1) active site. Int J Biol Macromol 119:352\u2013359","journal-title":"Int J Biol Macromol"},{"key":"763_CR138","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.848353","volume":"9","author":"M Tian","year":"2022","unstructured":"Tian M, Li H, Yan X, Gu J, Zheng P, Luo S, Zhangsun D, Chen Q, Ouyang Q (2022) Application of per-residue energy decomposition to design peptide inhibitors of PSD95 GK domain. Front Mol Biosci 9:848353","journal-title":"Front Mol Biosci"},{"key":"763_CR139","doi-asserted-by":"publisher","first-page":"2158","DOI":"10.1021\/acs.jcim.2c01641","volume":"63","author":"O Garland","year":"2023","unstructured":"Garland O, Ton A-T, Moradi S, Smith JR, Kovacic S, Ng K, Pandey M, Ban F, Lee J, Vuckovic M, Worrall LJ, Young RN, Pantophlet R, Strynadka NCJ, Cherkasov A (2023) Large-scale virtual screening for the discovery of SARS-CoV-2 papain-like protease (PLpro) non-covalent inhibitors. J Chem Inf Model 63:2158\u20132169","journal-title":"J Chem Inf Model"}],"container-title":["Journal of Computer-Aided Molecular Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-026-00763-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10822-026-00763-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-026-00763-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T04:50:06Z","timestamp":1770267006000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10822-026-00763-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,5]]},"references-count":139,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,12]]}},"alternative-id":["763"],"URL":"https:\/\/doi.org\/10.1007\/s10822-026-00763-z","relation":{},"ISSN":["0920-654X","1573-4951"],"issn-type":[{"value":"0920-654X","type":"print"},{"value":"1573-4951","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,5]]},"assertion":[{"value":"6 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest. The funding agencies had no involvement in the design of the study, data collection, analysis, interpretation of results, manuscript preparation, or the decision to publish.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"56"}}