{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:45:53Z","timestamp":1791859553221,"version":"4.3.4"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["In Silico Pharmacol."],"DOI":"10.1007\/s40203-026-00759-5","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:03:25Z","timestamp":1791817405000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering potent natural products against Sars-Cov-2 main protease using structure-based virtual screening and simulation studies"],"prefix":"10.1007","volume":"14","author":[{"given":"Pawan","family":"Gupta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishnu Kumar","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"issue":"2","key":"759_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1128\/mBio.00221-18","volume":"9","author":"ML Agostini","year":"2018","unstructured":"Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Denison MR (2018) Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. Mbio 9(2):10\u20131128","journal-title":"Mbio"},{"key":"759_CR2","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/prot.340170408","volume":"17","author":"A Amadei","year":"1993","unstructured":"Amadei A, Linssen AB, Berendsen HJ (1993) Essential dynamics of proteins. Proteins 17:412\u2013425","journal-title":"Proteins"},{"key":"759_CR3","doi-asserted-by":"publisher","first-page":"100128","DOI":"10.1016\/j.onehlt.2020.100128","volume":"9","author":"ES Amirian","year":"2020","unstructured":"Amirian ES, Levy JK (2020) Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health 9:100128","journal-title":"One Health"},{"issue":"4","key":"759_CR4","first-page":"519","volume":"12","author":"D Ang","year":"2023","unstructured":"Ang D, Kendall R, Atamian HS (2023) Virtual and in vitro screening of natural products identifies indole and benzene derivatives as inhibitors of SARS-CoV-2 Main Protease (Mpro). Biology (Basel) 12(4):519","journal-title":"Biology (Basel)"},{"issue":"12","key":"759_CR5","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.3390\/molecules31122156","volume":"31","author":"R Angelova","year":"2026","unstructured":"Angelova R, Stavrakov G, Spassov DS, Momekov G, Atanasova M (2026) Non-Classical Binding Mechanisms of Ferrocene-Modified Imatinib and Nilotinib Analogues in BCR-ABL1 Kinase Revealed by Computational Analysis. Molecules 31(12):2156","journal-title":"Molecules"},{"key":"759_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13063-017-2427-0","volume":"19","author":"YM Arabi","year":"2018","unstructured":"Arabi YM, Alothman A, Balkhy HH, Al-Dawood A, AlJohani S, Al Harbi S, Kojan S, Al Jeraisy M, Deeb AM, Assiri AM (2018) Treatment of Middle East respiratory syndrome with a combination of lopinavir-ritonavir and interferon-\u03b21b (MIRACLE trial): study protocol for a randomized controlled trial. Trials 19:1\u201313","journal-title":"Trials"},{"issue":"1","key":"759_CR7","doi-asserted-by":"publisher","first-page":"10795","DOI":"10.1038\/s41467-024-55031-1","volume":"15","author":"MM Aynaud","year":"2024","unstructured":"Aynaud MM, Caldwell L, Al-Zahrani KN, Barutcu S, Chan K, Obersterescu A, Ogunjimi AA, Jin M, Zakoor KR, Patel S, Padilla R (2024) Systematic surveillance of SARS-CoV-2 reveals dynamics of variant mutagenesis and transmission in a large urban population. Nat Commun 15(1):10795","journal-title":"Nat Commun"},{"key":"759_CR8","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1021\/acschemneuro.2c00738","volume":"14","author":"ATK Baidya","year":"2023","unstructured":"Baidya ATK, Das B, Devi B, L\u00e5ngstr\u00f6m B, \u00c5gren H, Darreh-Shori T, Kumar R (2023) Mechanistic insight into the inhibition of choline acetyltransferase by proton pump inhibitors. ACS Chem Neurosci 14:749\u2013765","journal-title":"ACS Chem Neurosci"},{"key":"759_CR9","doi-asserted-by":"crossref","unstructured":"Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD (2006) Scalable algorithms for molecular dynamics simulations on commodity clusters. Proceedings of the 2006 ACM\/IEEE Conference on Supercomputing, pp 84-es","DOI":"10.1145\/1188455.1188544"},{"issue":"5728","key":"759_CR10","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1126\/science.1110656","volume":"308","author":"K Chandran","year":"2005","unstructured":"Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM (2005) Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308(5728):1643\u20131645","journal-title":"Science"},{"issue":"10","key":"759_CR11","doi-asserted-by":"publisher","first-page":"e0240653","DOI":"10.1371\/journal.pone.0240653","volume":"15","author":"SA Cherrak","year":"2020","unstructured":"Cherrak SA, Merzouk H, Mokhtari-Soulimane N (2020) Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: a molecular docking and simulation studies. PLoS ONE 15(10):e0240653","journal-title":"PLoS ONE"},{"key":"759_CR12","doi-asserted-by":"publisher","first-page":"e200207","DOI":"10.1590\/0074-02760200207","volume":"115","author":"FM da Silva","year":"2020","unstructured":"da Silva FM, da Silva KP, de Oliveira LP, Costa EV, Koolen HH, Pinheiro ML, de Souza AQ, de Souza AD (2020) Flavonoid glycosides and their putative human metabolites as potential inhibitors of the SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). Mem Inst Oswaldo Cruz 115:e200207","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"759_CR13","doi-asserted-by":"crossref","unstructured":"David CC, Jacobs DJ (2014) Principal component analysis: a method for determining the essential dynamics of proteins. Protein dynamics: Methods and protocols:193-226","DOI":"10.1007\/978-1-62703-658-0_11"},{"key":"759_CR14","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1021\/acs.jmedchem.7b00717","volume":"61","author":"DA DeGoey","year":"2017","unstructured":"DeGoey DA, Chen H-J, Cox PB, Wendt MD (2017) Beyond the rule of 5: lessons learned from AbbVie\u2019s drugs and compound collection: miniperspective. J Med Chem 61:2636\u20132651","journal-title":"J Med Chem"},{"key":"759_CR15","doi-asserted-by":"publisher","first-page":"6679","DOI":"10.1021\/acsomega.2c07259","volume":"8","author":"CQ Duong","year":"2023","unstructured":"Duong CQ, Nguyen PTV (2023) Exploration of SARS-CoV-2 Mpro noncovalent natural inhibitors using structure-based approaches. ACS Omega 8:6679\u20136688","journal-title":"ACS Omega"},{"key":"759_CR16","doi-asserted-by":"publisher","first-page":"5781","DOI":"10.1021\/acs.jcim.0c00546","volume":"60","author":"A Gahlawat","year":"2020","unstructured":"Gahlawat A, Kumar N, Kumar R, Sandhu H, Singh IP, Singh S, Sj\u00f6stedt A, Garg P (2020) Structure-based virtual screening to discover potential lead molecules for the SARS-CoV-2 main protease. J Chem Inf Model 60:5781\u20135793","journal-title":"J Chem Inf Model"},{"issue":"5","key":"759_CR17","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1016\/j.bbagen.2014.09.007","volume":"1850","author":"R Galindo-Murillo","year":"2015","unstructured":"Galindo-Murillo R, Roe DR, Cheatham TE (2015) Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC). Biochimica Et Biophysica Acta (BBA) - General Subjects 1850(5):1041\u20131058","journal-title":"Biochimica Et Biophysica Acta (BBA) - General Subjects"},{"issue":"23","key":"759_CR18","doi-asserted-by":"publisher","first-page":"16922","DOI":"10.1021\/acs.jmedchem.1c00409","volume":"64","author":"K Gao","year":"2021","unstructured":"Gao K, Wang R, Chen J, Tepe JJ, Huang F, Wei GW (2021) Perspectives on SARS-CoV-2 main protease inhibitors. J Med Chem 64(23):16922\u201316955","journal-title":"J Med Chem"},{"issue":"5","key":"759_CR19","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(5):449\u2013461","journal-title":"Expert Opin Drug Discov"},{"key":"759_CR20","first-page":"148","volume":"65","author":"B Gim\u00e9nez","year":"2010","unstructured":"Gim\u00e9nez B, Santos M, Ferrarini M, Fernandes J (2010) Evaluation of blockbuster drugs under the rule-of-five. Die Pharmazie-an International Journal of Pharmaceutical Sciences 65:148\u2013152","journal-title":"Die Pharmazie-an International Journal of Pharmaceutical Sciences"},{"issue":"15","key":"759_CR21","doi-asserted-by":"publisher","first-page":"4773","DOI":"10.1074\/jbc.AC120.013056","volume":"295","author":"CJ Gordon","year":"2020","unstructured":"Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, G\u00f6tte M (2020) The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem 295(15):4773\u20134779","journal-title":"J Biol Chem"},{"issue":"1","key":"759_CR22","first-page":"1","volume":"32","author":"GC Gray","year":"2018","unstructured":"Gray GC, Vlasova AN, Lednicky JA, Nguyen-Tien T, Shittu I, Li F (2018) Emerging respiratory virus threats from influenza D and canine coronavirus HuPn-2018. Emerg Infect Dis 32(1):1","journal-title":"Emerg Infect Dis"},{"key":"759_CR23","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD014962.pub2","author":"F Grundeis","year":"2023","unstructured":"Grundeis F, Ansems K, Dahms K, Thieme V, Metzendorf MI, Skoetz N, Stegemann M (2023) Remdesivir for the treatment of COVID-19. The Cochrane Database of Systematic Reviews. https:\/\/doi.org\/10.1002\/14651858.CD014962.pub2","journal-title":"The Cochrane Database of Systematic Reviews"},{"issue":"4","key":"759_CR24","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1504\/IJCBDD.2023.130322","volume":"15","author":"P Gupta","year":"2023","unstructured":"Gupta P, Gupta S, Sinha S, Sundaram S, Sharma VK, Munshi A (2023) In silico phytochemical repurposing of natural molecules as entry inhibitors against RBD of the spike protein of SARS-CoV-2 using molecular docking studies. Int J Comput Biol Drug des 15(4):267\u2013288","journal-title":"Int J Comput Biol Drug des"},{"key":"759_CR25","doi-asserted-by":"publisher","first-page":"100496","DOI":"10.1016\/j.chphi.2024.100496","volume":"8","author":"P Gupta","year":"2024","unstructured":"Gupta P, Panwar U, Singh S (2024) Novel scaffolds identification against Mpro of SARS-CoV-2 using shape based screening and molecular simulation methods. Chem Phys Impact 8:100496","journal-title":"Chem Phys Impact"},{"issue":"15","key":"759_CR26","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1056\/NEJMoa2118542","volume":"386","author":"J Hammond","year":"2022","unstructured":"Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, Hendrick VM, Damle B, Sim\u00f3n-Campos A, Pypstra R (2022) Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 386(15):1397\u20131408","journal-title":"N Engl J Med"},{"key":"759_CR27","doi-asserted-by":"publisher","first-page":"3593","DOI":"10.1021\/acs.jcim.0c00283","volume":"60","author":"R Hatada","year":"2020","unstructured":"Hatada R, Okuwaki K, Mochizuki Y, Handa Y, Fukuzawa K, Komeiji Y, Okiyama Y, Tanaka S (2020) Fragment molecular orbital based interaction analyses on COVID-19 main protease\u2212 inhibitor N3 complex (PDB ID: 6LU7). J Chem Inf Model 60:3593\u20133602","journal-title":"J Chem Inf Model"},{"issue":"1","key":"759_CR28","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41392-023-01392-w","volume":"8","author":"C Huang","year":"2023","unstructured":"Huang C, Shuai H, Qiao J, Hou Y, Zeng R, Xia A, Xie L, Fang Z, Li Y, Yoon C, Huang Q (2023) A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants. Signal Transduct Target Ther 8(1):128","journal-title":"Signal Transduct Target Ther"},{"key":"759_CR29","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","volume":"582","author":"Z Jin","year":"2020","unstructured":"Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B et al (2020) Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 582:289\u2013293","journal-title":"Nature"},{"key":"759_CR30","doi-asserted-by":"publisher","first-page":"6474","DOI":"10.1021\/jp003919d","volume":"105","author":"GA Kaminski","year":"2001","unstructured":"Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. J Phys Chem B 105:6474\u20136487","journal-title":"J Phys Chem B"},{"key":"759_CR31","doi-asserted-by":"publisher","first-page":"100021","DOI":"10.1016\/j.arres.2021.100021","volume":"3","author":"Y Kato","year":"2021","unstructured":"Kato Y, Higashiyama A, Takaoka E, Nishikawa M, Ikushiro S (2021) Food phytochemicals, epigallocatechin gallate and myricetin, covalently bind to the active site of the coronavirus main protease in vitro. Adv Redox Res 3:100021","journal-title":"Adv Redox Res"},{"key":"759_CR32","first-page":"2020030226","volume":"2020","author":"S Khaerunnisa","year":"2020","unstructured":"Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S, Soetjipto S (2020) Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints 2020:2020030226","journal-title":"Preprints"},{"key":"759_CR33","doi-asserted-by":"publisher","first-page":"2841","DOI":"10.1002\/ptr.6998","volume":"35","author":"A Khan","year":"2021","unstructured":"Khan A, Heng W, Wang Y, Qiu J, Wei X, Peng S, Saleem S, Khan M, Ali SS, Wei DQ (2021) In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS\u2010CoV\u20102 main protease (3CLpro). Phytother Res 35:2841","journal-title":"Phytother Res"},{"key":"759_CR34","doi-asserted-by":"publisher","first-page":"e1005531","DOI":"10.1371\/journal.ppat.1005531","volume":"12","author":"Y Kim","year":"2016","unstructured":"Kim Y, Liu H, Galasiti Kankanamalage AC, Weerasekara S, Hua DH, Groutas WC, Chang K-O, Pedersen NC (2016) Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor. PLoS Pathog 12:e1005531","journal-title":"PLoS Pathog"},{"key":"759_CR35","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1080\/08927029408021981","volume":"13","author":"A Lemak","year":"1994","unstructured":"Lemak A, Balabaev N (1994) On the Berendsen thermostat. Mol Simul 13:177\u2013187","journal-title":"Mol Simul"},{"key":"759_CR36","doi-asserted-by":"publisher","first-page":"118","DOI":"10.3389\/fcimb.2020.00118","volume":"10","author":"C Liu","year":"2020","unstructured":"Liu C, Yin J, Yao J, Xu Z, Tao Y, Zhang H (2020) Pharmacophore-based virtual screening toward the discovery of novel anti-echinococcal compounds. Front Cell Infect Microbiol 10:118","journal-title":"Front Cell Infect Microbiol"},{"issue":"8","key":"759_CR37","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.2174\/1570180820666230224112505","volume":"21","author":"N Lohit","year":"2024","unstructured":"Lohit N, Singh AK, Kumar A, Singh H, Yadav JP, Singh K, Kumar P (2024) Description and in silico ADME studies of US-FDA approved drugs or drugs under clinical trial which violate the Lipinski\u2019s rule of 5. Lett Drug des Discov 21(8):1334\u20131358","journal-title":"Lett Drug des Discov"},{"key":"759_CR38","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1002\/jmv.25678","volume":"92","author":"H Lu","year":"2020","unstructured":"Lu H, Stratton CW, Tang YW (2020) Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle. J Med Virol 92:401\u2013402","journal-title":"J Med Virol"},{"key":"759_CR39","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.bj.2020.11.005","volume":"44","author":"P Magro","year":"2021","unstructured":"Magro P, Zanella I, Pescarolo M, Castelli F, Quiros-Roldan E (2021) Lopinavir\/ritonavir: repurposing an old drug for HIV infection in COVID-19 treatment. Biomed J 44:43\u201353","journal-title":"Biomed J"},{"key":"759_CR40","doi-asserted-by":"publisher","first-page":"3802","DOI":"10.1080\/07391102.2020.1768902","volume":"39","author":"S Mahanta","year":"2021","unstructured":"Mahanta S, Chowdhury P, Gogoi N, Goswami N, Borah D, Kumar R, Chetia D, Borah P, Buragohain AK, Gogoi B (2021) Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: an in silico based approach. J Biomol Struct Dyn 39:3802\u20133811","journal-title":"J Biomol Struct Dyn"},{"key":"759_CR41","doi-asserted-by":"publisher","first-page":"6710","DOI":"10.3390\/molecules27196710","volume":"27","author":"RE Mahgoub","year":"2022","unstructured":"Mahgoub RE, Mohamed FE, Alzyoud L, Ali BR, Ferreira J, Rabeh WM, AlNeyadi SS, Atatreh N, Ghattas MA (2022) The discovery of small allosteric and active site inhibitors of the SARS-CoV-2 main protease via structure-based virtual screening and biological evaluation. Molecules 27:6710","journal-title":"Molecules"},{"key":"759_CR42","doi-asserted-by":"publisher","first-page":"9954","DOI":"10.1021\/jp003020w","volume":"105","author":"P Mark","year":"2001","unstructured":"Mark P, Nilsson L (2001) Structure and dynamics of the TIP3P, SPC, and SPC\/E water models at 298 K. J Phys Chem A 105:9954\u20139960","journal-title":"J Phys Chem A"},{"key":"759_CR43","doi-asserted-by":"publisher","first-page":"109245","DOI":"10.1016\/j.compbiomed.2024.109245","volume":"183","author":"S Moradi","year":"2024","unstructured":"Moradi S, Nowroozi A, Nezhad MA, Jalali P, Khosravi R, Shahlaei M (2024) A review on description dynamics and conformational changes of proteins using combination of principal component analysis and molecular dynamics simulation. Comput Biol Med 183:109245","journal-title":"Comput Biol Med"},{"key":"759_CR44","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.2174\/1568026620666200704135327","volume":"20","author":"A Nayarisseri","year":"2020","unstructured":"Nayarisseri A, Khandelwal R, Madhavi M, Selvaraj C, Panwar U, Sharma K, Hussain T, Singh SK (2020) Shape-based machine learning models for the potential novel COVID-19 protease inhibitors assisted by molecular dynamics simulation. Curr Top Med Chem 20:2146\u20132167","journal-title":"Curr Top Med Chem"},{"key":"759_CR45","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1021\/acs.biochem.0c00160","volume":"59","author":"B Nutho","year":"2020","unstructured":"Nutho B, Mahalapbutr P, Hengphasatporn K, Pattaranggoon NC, Simanon N, Shigeta Y, Hannongbua S, Rungrotmongkol T (2020) Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms. Biochemistry 59:1769\u20131779","journal-title":"Biochemistry"},{"issue":"1","key":"759_CR46","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s42004-024-01114-5","volume":"7","author":"F Orme\u00f1o","year":"2024","unstructured":"Orme\u00f1o F, General IJ (2024) Convergence and equilibrium in molecular dynamics simulations. Commun Chem 7(1):32","journal-title":"Commun Chem"},{"key":"759_CR47","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1126\/science.abl4784","volume":"374","author":"DR Owen","year":"2021","unstructured":"Owen DR et al (2021) An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374:1586\u20131593","journal-title":"Science"},{"issue":"11","key":"759_CR48","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.3390\/molecules21111556","volume":"21","author":"S Park","year":"2016","unstructured":"Park S (2016) Cyclic glucans enhance solubility of bioavailable flavonoids. Molecules 21(11):1556","journal-title":"Molecules"},{"issue":"1","key":"759_CR49","doi-asserted-by":"publisher","first-page":"20295","DOI":"10.1038\/s41598-021-99165-4","volume":"11","author":"CN Patel","year":"2021","unstructured":"Patel CN, Jani SP, Jaiswal DG, Kumar SP, Mangukia N, Parmar RM, Rawal RM, Pandya HA (2021) Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations. Sci Rep 11(1):20295","journal-title":"Sci Rep"},{"issue":"10","key":"759_CR50","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1021\/acs.jcim.6b00347","volume":"56","author":"JJ Perez","year":"2016","unstructured":"Perez JJ, Tomas MS, Rubio-Martinez J (2016) Assessment of the sampling performance of multiple-copy dynamics versus a unique trajectory. J Chem Inf Model 56(10):1950\u20131962","journal-title":"J Chem Inf Model"},{"key":"759_CR51","doi-asserted-by":"publisher","first-page":"e1000415","DOI":"10.1371\/journal.pcbi.1000415","volume":"5","author":"D Prada-Gracia","year":"2009","unstructured":"Prada-Gracia D, G\u00f3mez-Garde\u00f1es J, Echenique P, Falo F (2009) Exploring the free energy landscape: from dynamics to networks and back. PLoS Comput Biol 5:e1000415","journal-title":"PLoS Comput Biol"},{"key":"759_CR52","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrd.2018.168","volume":"18","author":"S Pushpakom","year":"2019","unstructured":"Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18:41\u201358","journal-title":"Nat Rev Drug Discov"},{"key":"759_CR53","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.jsbmb.2018.09.001","volume":"185","author":"VW-H Rabelo","year":"2019","unstructured":"Rabelo VW-H, de Jesus VD, Tucci EMN, Romeiro NC, Abreu PA (2019) Virtual screening and drug repositioning as strategies for the discovery of new antifungal inhibitors of oxidosqualene cyclase. J Steroid Biochem Mol Biol 185:189\u2013199","journal-title":"J Steroid Biochem Mol Biol"},{"key":"759_CR54","doi-asserted-by":"publisher","first-page":"234","DOI":"10.3109\/10799893.2013.789912","volume":"33","author":"KK Reddy","year":"2013","unstructured":"Reddy KK, Singh SK, Tripathi SK, Selvaraj C, Suryanarayanan V (2013) Shape and pharmacophore-based virtual screening to identify potential cytochrome P450 sterol 14\u03b1-demethylase inhibitors. J Recept Signal Transduct 33:234\u2013243","journal-title":"J Recept Signal Transduct"},{"key":"759_CR55","doi-asserted-by":"publisher","first-page":"140286","DOI":"10.1016\/j.molstruc.2024.140286","volume":"1321","author":"S Ren","year":"2025","unstructured":"Ren S, Liu X, Huang Y, Zhu C, Zhu W, Dong H (2025) Flavonoids as potential SARS-CoV-2 main protease inhibitors: in vitro activity evaluation, molecular docking, 3D-QSAR investigation and synthesis. J Mol Struct 1321:140286","journal-title":"J Mol Struct"},{"key":"759_CR56","doi-asserted-by":"publisher","first-page":"1336001","DOI":"10.3389\/fchem.2024.1336001","volume":"12","author":"JAP da Rocha","year":"2024","unstructured":"da Rocha JAP, da Costa RA, da Costa ADSS, da Rocha ECM, Gomes AJB, Machado AK, Lima e Lima, A. H. (2024) Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation. Front Chem 12:1336001","journal-title":"Front Chem"},{"issue":"12","key":"759_CR57","doi-asserted-by":"publisher","first-page":"6094","DOI":"10.1021\/acs.jcim.1c00951","volume":"61","author":"J Rubio-Mart\u00ednez","year":"2021","unstructured":"Rubio-Mart\u00ednez J, Jim\u00e9nez-Alesanco A, Ceballos-Laita L, Ortega-Alarc\u00f3n D, Vega S, Calvo C, Ben\u00edtez C, Abian O, Vel\u00e1zquez-Campoy A, Thomson TM, Granadino-Rold\u00e1n JM (2021) Discovery of diverse natural products as inhibitors of SARS-CoV-2 Mpro protease through virtual screening. J Chem Inf Model 61(12):6094","journal-title":"J Chem Inf Model"},{"issue":"8","key":"759_CR58","doi-asserted-by":"publisher","first-page":"4174","DOI":"10.1128\/JVI.80.8.4174-4178.2006","volume":"80","author":"K Schornberg","year":"2006","unstructured":"Schornberg K, Matsuyama S, Kabsch K, Delos S, Bouton A, White J (2006) Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J Virol 80(8):4174\u20134178","journal-title":"J Virol"},{"key":"759_CR59","unstructured":"Schr\u00f6dinger, LLC, New York, NY, 2024 \u20133."},{"key":"759_CR60","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1089\/adt.2019.939","volume":"17","author":"S Sharma","year":"2019","unstructured":"Sharma S, Gupta J, Prabhakar PK, Gupta P, Solanki P, Rajput A (2019) Phytochemical repurposing of natural molecule: sabinene for identification of novel therapeutic benefits using in silico and in vitro approaches. Assay Drug Dev Technol 17:339\u2013351","journal-title":"Assay Drug Dev Technol"},{"key":"759_CR61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-13940-6","volume":"11","author":"TP Sheahan","year":"2020","unstructured":"Sheahan TP, Sims AC, Leist SR, Sch\u00e4fer A, Won J, Brown AJ, Montgomery SA, Hogg A, Babusis D, Clarke MO (2020) Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 11:1\u201314","journal-title":"Nat Commun"},{"key":"759_CR62","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1021\/ct900587b","volume":"6","author":"D Shivakumar","year":"2010","unstructured":"Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W (2010) Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 6:1509\u20131519","journal-title":"J Chem Theory Comput"},{"issue":"12","key":"759_CR63","doi-asserted-by":"publisher","first-page":"4240","DOI":"10.1073\/pnas.0306446101","volume":"101","author":"G Simmons","year":"2004","unstructured":"Simmons G, Reeves JD, Rennekamp AJ, Amberg SM, Piefer AJ, Bates P (2004) Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc Natl Acad Sci U S A 101(12):4240\u20134245","journal-title":"Proc Natl Acad Sci U S A"},{"key":"759_CR64","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1080\/07391102.2015.1116411","volume":"34","author":"S Singh","year":"2016","unstructured":"Singh S, Vijaya Prabhu S, Suryanarayanan V, Bhardwaj R, Singh SK, Dubey VK (2016) Molecular docking and structure-based virtual screening studies of potential drug target, CAAX prenyl proteases, of Leishmania donovani. J Biomol Struct Dyn 34:2367\u20132386","journal-title":"J Biomol Struct Dyn"},{"key":"759_CR65","doi-asserted-by":"publisher","first-page":"619","DOI":"10.2174\/1570163816666190321142826","volume":"17","author":"S Singh","year":"2020","unstructured":"Singh S, Gupta P, Gupta J (2020) Virtual structural similarity elucidates bioactivity of Fenchone: enriched phytochemical in fennel essential oil. Curr Drug Discov Technol 17:619\u2013630","journal-title":"Curr Drug Discov Technol"},{"issue":"6","key":"759_CR66","doi-asserted-by":"publisher","first-page":"106004","DOI":"10.1016\/j.ijantimicag.2020.106004","volume":"55","author":"SP Smieszek","year":"2020","unstructured":"Smieszek SP, Przychodzen BP, Polymeropoulos MH (2020) Amantadine disrupts lysosomal gene expression: a hypothesis for COVID19 treatment. Int J Antimicrob Agents 55(6):106004","journal-title":"Int J Antimicrob Agents"},{"key":"759_CR67","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/978-1-4939-8955-3_2","volume-title":"Computational methods for drug repurposing","author":"F Sohraby","year":"2019","unstructured":"Sohraby F, Bagheri M, Aryapour H (2019) Performing an in silico repurposing of existing drugs by combining virtual screening and molecular dynamics simulation. Computational methods for drug repurposing. Springer, pp 23\u201343"},{"issue":"23","key":"759_CR68","doi-asserted-by":"publisher","first-page":"5513","DOI":"10.3390\/molecules29235513","volume":"29","author":"D Swiatla-Wojcik","year":"2024","unstructured":"Swiatla-Wojcik D (2024) Simulation studies of the dynamics and the connectivity patterns of hydrogen bonds in water from ambient to supercritical conditions. Molecules 29(23):5513","journal-title":"Molecules"},{"key":"759_CR69","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1080\/17460441.2020.1704729","volume":"15","author":"A Talevi","year":"2020","unstructured":"Talevi A, Bellera CL (2020) Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics. Expert Opin Drug Discov 15:397\u2013401","journal-title":"Expert Opin Drug Discov"},{"issue":"2","key":"759_CR70","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1021\/np010466a","volume":"65","author":"Y Tang","year":"2002","unstructured":"Tang Y, Yu B, Hu J, Wu T, Hui H (2002) Three new homoisoflavanone glycosides from the bulbs of Ornithogalum caudatum. J Nat Prod 65(2):218\u2013220","journal-title":"J Nat Prod"},{"issue":"9","key":"759_CR71","doi-asserted-by":"publisher","first-page":"3367","DOI":"10.3390\/nu5093367","volume":"5","author":"SH Thilakarathna","year":"2013","unstructured":"Thilakarathna SH, Rupasinghe HV (2013) Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 5(9):3367\u20133387","journal-title":"Nutrients"},{"key":"759_CR72","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.jtbi.2013.05.014","volume":"334","author":"SK Tripathi","year":"2013","unstructured":"Tripathi SK, Muttineni R, Singh SK (2013) Extra precision docking, free energy calculation and molecular dynamics simulation studies of CDK2 inhibitors. J Theor Biol 334:87\u2013100","journal-title":"J Theor Biol"},{"issue":"7","key":"759_CR73","doi-asserted-by":"publisher","first-page":"7003","DOI":"10.1021\/acs.jmedchem.4c02561","volume":"68","author":"JB Tuttle","year":"2025","unstructured":"Tuttle JB, Allais C, Allerton CM, Anderson AS, Arcari JT, Aschenbrenner LM, Avery M, Bellenger J, Berritt S, Boras B, Boscoe BP (2025) Discovery of Nirmatrelvir (PF-07321332): A potent, orally active inhibitor of the severe acute respiratory syndrome Coronavirus 2 (SARS CoV-2) main protease. J Med Chem 68(7):7003\u20137030","journal-title":"J Med Chem"},{"key":"759_CR74","doi-asserted-by":"publisher","first-page":"3609","DOI":"10.1080\/07391102.2020.1848636","volume":"40","author":"A Uniyal","year":"2022","unstructured":"Uniyal A, Mahapatra MK, Tiwari V, Sandhir R, Kumar R (2022) Targeting SARS-CoV-2 main protease: structure based virtual screening, in silico ADMET studies and molecular dynamics simulation for identification of potential inhibitors. J Biomol Struct Dyn 40:3609\u20133625","journal-title":"J Biomol Struct Dyn"},{"key":"759_CR75","doi-asserted-by":"publisher","first-page":"105252","DOI":"10.1016\/j.antiviral.2022.105252","volume":"198","author":"L Vangeel","year":"2022","unstructured":"Vangeel L, Chiu W, De Jonghe S, Maes P, Slechten B, Raymenants J, Andr\u00e9 E, Leyssen P, Neyts J, Jochmans D (2022) Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antivir Res 198:105252","journal-title":"Antivir Res"},{"key":"759_CR76","first-page":"73","volume":"5","author":"J Wang","year":"2004","unstructured":"Wang J, Urban L (2004) The impact of early ADME profiling on drug discovery and development strategy. DDW Drug Discov World 5:73\u201386","journal-title":"DDW Drug Discov World"},{"key":"759_CR77","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","volume":"582","author":"KY Wang","year":"2020","unstructured":"Wang KY, Liu F, Jiang R, Yang X, You T, Liu X, Xiao CQ, Shi Z, Jiang H, Rao Z (2020) Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature 582:289\u2013293","journal-title":"Nature"},{"issue":"7594","key":"759_CR78","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nature17180","volume":"531","author":"TK Warren","year":"2016","unstructured":"Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531(7594):381\u2013385","journal-title":"Nature"},{"key":"759_CR79","doi-asserted-by":"publisher","first-page":"8408","DOI":"10.1021\/jp404160y","volume":"117","author":"L Xu","year":"2013","unstructured":"Xu L, Sun H, Li Y, Wang J, Hou T (2013) Assessing the performance of MM\/PBSA and MM\/GBSA methods. 3. The impact of force fields and ligand charge models. J Phys Chem B 117:8408\u20138421","journal-title":"J Phys Chem B"},{"issue":"8","key":"759_CR80","doi-asserted-by":"publisher","first-page":"4021","DOI":"10.1021\/acs.jcim.0c00580","volume":"60","author":"T Yasuda","year":"2020","unstructured":"Yasuda T, Shigeta Y, Harada R (2020) Efficient conformational sampling of collective motions of proteins with principal component analysis-based parallel cascade selection molecular dynamics. J Chem Inf Model 60(8):4021\u20134029","journal-title":"J Chem Inf Model"},{"key":"759_CR81","doi-asserted-by":"publisher","first-page":"1125246","DOI":"10.3389\/fimmu.2023.1125246","volume":"14","author":"Y Yuan","year":"2023","unstructured":"Yuan Y, Jiao B, Qu L, Yang D, Liu R (2023) The development of COVID-19 treatment. Front Immunol 14:1125246","journal-title":"Front Immunol"},{"issue":"7","key":"759_CR82","doi-asserted-by":"publisher","first-page":"797","DOI":"10.3390\/biom14070797","volume":"14","author":"A Zag\u00f3rska","year":"2024","unstructured":"Zag\u00f3rska A, Czopek A, Fryc M, Jo\u0144czyk J (2024) Inhibitors of SARS-CoV-2 main protease (Mpro) as anti-coronavirus agents. Biomolecules 14(7):797","journal-title":"Biomolecules"},{"key":"759_CR83","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2026.117791","author":"X Zhang","year":"2020","unstructured":"Zhang X, Xu Y, Jiang Y, Huang J, Li X (2020) From 2020 to 2025: comprehensive review decoding novel structural inhibitors for Mpro of SARS-CoV-2. Biochem Pharmacol. https:\/\/doi.org\/10.1016\/j.bcp.2026.117791","journal-title":"Biochem Pharmacol"},{"issue":"5","key":"759_CR84","first-page":"275","volume":"49","author":"Z Zheng","year":"2024","unstructured":"Zheng Z, Zhou J, Song Y (2024) Safety of RNA-dependent RNA polymerase inhibitors, Molnupiravir and VV116, for oral treatment of COVID-19: a meta-analysis. Iran J Med Sci 49(5):275","journal-title":"Iran J Med Sci"},{"key":"759_CR85","doi-asserted-by":"publisher","first-page":"601316","DOI":"10.3389\/fpls.2020.601316","volume":"11","author":"Y Zhu","year":"2020","unstructured":"Zhu Y, Xie DY (2020) Docking characterization and in vitro inhibitory activity of flavan-3-ols and dimeric proanthocyanidins against the main protease activity of SARS-CoV-2. Front Plant Sci 11:601316","journal-title":"Front Plant Sci"},{"key":"759_CR86","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nrd.2015.37","volume":"15","author":"A Zumla","year":"2016","unstructured":"Zumla A, Chan JF, Azhar EI, Hui DS, Yuen K-Y (2016) Coronaviruses\u2014drug discovery and therapeutic options. Nat Rev Drug Discov 15:327\u2013347","journal-title":"Nat Rev Drug Discov"}],"container-title":["In Silico Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40203-026-00759-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40203-026-00759-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40203-026-00759-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:02:17Z","timestamp":1791856937000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40203-026-00759-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,12]]},"references-count":86,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["759"],"URL":"https:\/\/doi.org\/10.1007\/s40203-026-00759-5","relation":{},"ISSN":["2193-9616"],"issn-type":[{"value":"2193-9616","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,12]]},"assertion":[{"value":"11 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"None.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}],"article-number":"257"}}