{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T19:22:08Z","timestamp":1775848928731,"version":"3.50.1"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T00:00:00Z","timestamp":1610928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T00:00:00Z","timestamp":1610928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["675899"],"award-info":[{"award-number":["675899"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","award":["2017-1.2.1-NKP-2017-00002"],"award-info":[{"award-number":["2017-1.2.1-NKP-2017-00002"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["K111862"],"award-info":[{"award-number":["K111862"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["PD124598"],"award-info":[{"award-number":["PD124598"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","award":["Z1-1859"],"award-info":[{"award-number":["Z1-1859"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","award":["P1-0208"],"award-info":[{"award-number":["P1-0208"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","award":["L1-8157"],"award-info":[{"award-number":["L1-8157"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ELKH Research Centre for Natural Sciences"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Comput Aided Mol Des"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies the reactive docking method (Backus et al. in Nature 534:570\u2013574, 2016) and extends it into a virtual screening tool by introducing facile experimental or computational parametrization and a ligand focused evaluation scheme together with a retrospective and prospective validation against various therapeutically relevant targets. Parameters accounting for ligand reactivity are derived from experimental reaction kinetic data or alternatively from computed reaction barriers. The performance of this docking protocol was first evaluated by investigating compound series with diverse warhead chemotypes against KRAS<jats:sup>G12C<\/jats:sup>, MurA and cathepsin B. In addition, WIDOCK was challenged on larger electrophilic libraries screened against OTUB2 and NUDT7. These retrospective analyses showed high sensitivity in retrieving experimental actives, by also leading to superior ROC curves, AUC values and better enrichments than the standard covalent docking tool available in AutoDock4 when compound collections with diverse warheads were investigated. Finally, we applied WIDOCK for the prospective identification of covalent human MAO-A inhibitors acting via a new mechanism by binding to Cys323. The inhibitory activity of several predicted compounds was experimentally confirmed and the labelling of Cys323 was proved by subsequent MS\/MS measurements. These findings demonstrate the usefulness of WIDOCK as a warhead-sensitive, covalent virtual screening protocol.<\/jats:p>","DOI":"10.1007\/s10822-020-00371-5","type":"journal-article","created":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T02:02:31Z","timestamp":1610935351000},"page":"223-244","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors"],"prefix":"10.1007","volume":"35","author":[{"given":"Andrea","family":"Scarpino","sequence":"first","affiliation":[]},{"given":"L\u00e1szl\u00f3","family":"Petri","sequence":"additional","affiliation":[]},{"given":"Damijan","family":"Knez","sequence":"additional","affiliation":[]},{"given":"T\u00edmea","family":"Imre","sequence":"additional","affiliation":[]},{"given":"P\u00e9ter","family":"\u00c1br\u00e1nyi-Balogh","sequence":"additional","affiliation":[]},{"given":"Gy\u00f6rgy G.","family":"Ferenczy","sequence":"additional","affiliation":[]},{"given":"Stanislav","family":"Gobec","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1039-7809","authenticated-orcid":false,"given":"Gy\u00f6rgy M.","family":"Keser\u0171","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,1,18]]},"reference":[{"key":"371_CR1","doi-asserted-by":"publisher","first-page":"13408","DOI":"10.1002\/anie.201601091","volume":"55","author":"TA Baillie","year":"2016","unstructured":"Baillie TA (2016) Targeted covalent inhibitors for drug design. Angew Chem Int Ed 55:13408\u201313421. https:\/\/doi.org\/10.1002\/anie.201601091","journal-title":"Angew Chem Int Ed"},{"key":"371_CR2","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1038\/nrd3410","volume":"10","author":"J Singh","year":"2011","unstructured":"Singh J, Petter RC, Baillie TA, Whitty A (2011) The resurgence of covalent drugs. Nat Rev Drug Discov 10:307\u2013317. https:\/\/doi.org\/10.1038\/nrd3410","journal-title":"Nat Rev Drug Discov"},{"key":"371_CR3","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.drudis.2015.05.005","volume":"20","author":"RA Bauer","year":"2015","unstructured":"Bauer RA (2015) Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discov Today 20:1061\u20131073. https:\/\/doi.org\/10.1016\/j.drudis.2015.05.005","journal-title":"Drug Discov Today"},{"key":"371_CR4","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.cbpa.2014.10.021","volume":"24","author":"DA Shannon","year":"2015","unstructured":"Shannon DA, Weerapana E (2015) Covalent protein modification: the current landscape of residue-specific electrophiles. Curr Opin Chem Biol 24:18\u201326. https:\/\/doi.org\/10.1016\/j.cbpa.2014.10.021","journal-title":"Curr Opin Chem Biol"},{"key":"371_CR5","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1021\/jm800498e","volume":"52","author":"AJT Smith","year":"2009","unstructured":"Smith AJT, Zhang X, Leach AG, Houk KN (2009) Beyond picomolar affinities: quantitative aspects of noncovalent and covalent binding of drugs to proteins. J Med Chem 52:225\u2013233. https:\/\/doi.org\/10.1021\/jm800498e","journal-title":"J Med Chem"},{"key":"371_CR6","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1002\/cmdc.201500469","volume":"11","author":"C Gonz\u00e1lez-Bello","year":"2016","unstructured":"Gonz\u00e1lez-Bello C (2016) Designing irreversible inhibitors-worth the effort? ChemMedChem 11:22\u201330. https:\/\/doi.org\/10.1002\/cmdc.201500469","journal-title":"ChemMedChem"},{"key":"371_CR7","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.ejmech.2017.06.019","volume":"138","author":"S De Cesco","year":"2017","unstructured":"De Cesco S, Kurian J, Dufresne C, Mittermaier AK, Moitessier N (2017) Covalent inhibitors design and discovery. Eur J Med Chem 138:96\u2013114. https:\/\/doi.org\/10.1016\/j.ejmech.2017.06.019","journal-title":"Eur J Med Chem"},{"key":"371_CR8","doi-asserted-by":"publisher","first-page":"3326","DOI":"10.1021\/acs.biochem.8b00315","volume":"57","author":"A Tuley","year":"2018","unstructured":"Tuley A, Fast W (2018) The taxonomy of covalent inhibitors. Biochemistry 57:3326\u20133337. https:\/\/doi.org\/10.1021\/acs.biochem.8b00315","journal-title":"Biochemistry"},{"key":"371_CR9","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.ejmech.2018.10.010","volume":"160","author":"P \u00c1br\u00e1nyi-Balogh","year":"2018","unstructured":"\u00c1br\u00e1nyi-Balogh P, Petri L, Imre T, Szijj P, Scarpino A, Hrast M, Mitrovi\u0107 A, Fonovi\u010d UP, N\u00e9meth K, Barreteau H, Roper DI, Horv\u00e1ti K, Ferenczy GG, Kos J, Ila\u0161 J, Gobec S, Keser\u0171 GM (2018) A road map for prioritizing warheads for cysteine targeting covalent inhibitors. Eur J Med Chem 160:94\u2013107. https:\/\/doi.org\/10.1016\/j.ejmech.2018.10.010","journal-title":"Eur J Med Chem"},{"key":"371_CR10","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. https:\/\/doi.org\/10.1006\/JMBI.1996.0897","journal-title":"J Mol Biol"},{"key":"371_CR11","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1002\/prot.10465","volume":"52","author":"ML Verdonk","year":"2003","unstructured":"Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein-ligand docking using GOLD. Proteins Struct Funct Bioinform 52:609\u2013623. https:\/\/doi.org\/10.1002\/prot.10465","journal-title":"Proteins Struct Funct Bioinform"},{"key":"371_CR12","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1021\/ci034289q","volume":"44","author":"ML Verdonk","year":"2004","unstructured":"Verdonk ML, Berdini V, Hartshorn MJ, Mooij WTM, Murray CW, Taylor RD, Watson P (2004) Virtual screening using protein\u2212ligand docking: avoiding artificial enrichment. J Chem Inf Comput Sci 44:793\u2013806. https:\/\/doi.org\/10.1021\/ci034289q","journal-title":"J Chem Inf Comput Sci"},{"key":"371_CR13","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. https:\/\/doi.org\/10.1002\/jcc.21256","journal-title":"J Comput Chem"},{"key":"371_CR14","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/pro.2733","volume":"25","author":"G Bianco","year":"2016","unstructured":"Bianco G, Forli S, Goodsell DS, Olson AJ (2016) Covalent docking using Autodock: two-point attractor and flexible side chain methods. Protein Sci 25:295\u2013301. https:\/\/doi.org\/10.1002\/pro.2733","journal-title":"Protein Sci"},{"key":"371_CR15","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1002\/jcc.540150503","volume":"15","author":"R Abagyan","year":"1994","unstructured":"Abagyan R, Totrov M, Kuznetsov D (1994) ICM\u2014a new method for protein modeling and design: applications to docking and structure prediction from the distorted native conformation. J Comput Chem 15:488\u2013506. https:\/\/doi.org\/10.1002\/jcc.540150503","journal-title":"J Comput Chem"},{"key":"371_CR16","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1007\/s10822-007-9138-7","volume":"21","author":"V Katritch","year":"2007","unstructured":"Katritch V, Byrd CM, Tseitin V, Dai D, Raush E, Totrov M, Abagyan R, Jordan R, Hruby DE (2007) Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches. J Comput Aided Mol Des 21:549\u2013558. https:\/\/doi.org\/10.1007\/s10822-007-9138-7","journal-title":"J Comput Aided Mol Des"},{"key":"371_CR17","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1021\/ci500118s","volume":"54","author":"K Zhu","year":"2014","unstructured":"Zhu K, Borrelli KW, Greenwood JR, Day T, Abel R, Farid RS, Harder E (2014) Docking covalent inhibitors: a parameter free approach to pose prediction and scoring. J Chem Inf Model 54:1932\u20131940. https:\/\/doi.org\/10.1021\/ci500118s","journal-title":"J Chem Inf Model"},{"key":"371_CR18","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1021\/ci500175r","volume":"54","author":"D Toledo Warshaviak","year":"2014","unstructured":"Toledo Warshaviak D, Golan G, Borrelli KW, Zhu K, Kalid O (2014) Structure-based virtual screening approach for discovery of covalently bound ligands. J Chem Inf Model 54:1941\u20131950. https:\/\/doi.org\/10.1021\/ci500175r","journal-title":"J Chem Inf Model"},{"key":"371_CR19","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1038\/nature18002","volume":"534","author":"KM Backus","year":"2016","unstructured":"Backus KM, Correia BE, Lum KM, Forli S, Horning BD, Gonz\u00e1lez-P\u00e1ez GE, Chatterjee S, Lanning BR, Teijaro JR, Olson AJ, Wolan DW, Cravatt BF (2016) Proteome-wide covalent ligand discovery in native biological systems. Nature 534:570\u2013574. https:\/\/doi.org\/10.1038\/nature18002","journal-title":"Nature"},{"key":"371_CR20","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1021\/ci700036j","volume":"47","author":"S Forli","year":"2007","unstructured":"Forli S, Botta M (2007) Lennard-Jones potential and dummy atom settings to overcome the AUTODOCK limitation in treating flexible ring systems. J Chem Inf Model 47:1481\u20131492. https:\/\/doi.org\/10.1021\/ci700036j","journal-title":"J Chem Inf Model"},{"key":"371_CR21","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1021\/jacs.7b08366","volume":"140","author":"DE Mortenson","year":"2018","unstructured":"Mortenson DE, Brighty GJ, Plate L, Bare G, Chen W, Li S, Wang H, Cravatt BF, Forli S, Powers ET, Sharpless KB, Wilson IA, Kelly JW (2018) \u201cInverse drug discovery\u201d strategy to identify proteins that are targeted by latent electrophiles as exemplified by aryl fluorosulfates. J Am Chem Soc 140:200\u2013210. https:\/\/doi.org\/10.1021\/jacs.7b08366","journal-title":"J Am Chem Soc"},{"key":"371_CR22","doi-asserted-by":"publisher","first-page":"18808","DOI":"10.1073\/pnas.1909972116","volume":"116","author":"Q Zheng","year":"2019","unstructured":"Zheng Q, Woehl JL, Kitamura S, Santos-Martins D, Smedley CJ, Li G, Forli S, Moses JE, Wolan DW, Barry Sharpless K (2019) SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase. Proc Natl Acad Sci USA 116:18808\u201318814. https:\/\/doi.org\/10.1073\/pnas.1909972116","journal-title":"Proc Natl Acad Sci USA"},{"key":"371_CR23","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1021\/acs.jcim.8b00228","volume":"58","author":"A Scarpino","year":"2018","unstructured":"Scarpino A, Ferenczy GG, Keser\u0171 GM (2018) Comparative evaluation of covalent docking tools. J Chem Inf Model 58:1441\u20131458. https:\/\/doi.org\/10.1021\/acs.jcim.8b00228","journal-title":"J Chem Inf Model"},{"key":"371_CR24","doi-asserted-by":"publisher","first-page":"3565","DOI":"10.1021\/acs.jcim.9b00316","volume":"59","author":"F Palazzesi","year":"2019","unstructured":"Palazzesi F, Grundl M, Pautsch A, Weber A, Tautermann C (2019) A fast ab initio predictor tool for covalent reactivity estimation of acrylamides. J Chem Inf Model 59:3565\u20133571. https:\/\/doi.org\/10.1021\/acs.jcim.9b00316","journal-title":"J Chem Inf Model"},{"key":"371_CR25","doi-asserted-by":"publisher","first-page":"3178","DOI":"10.1021\/acs.biochem.7b00271","volume":"56","author":"LM McGregor","year":"2017","unstructured":"McGregor LM, Jenkins ML, Kerwin C, Burke JE, Shokat KM (2017) Expanding the scope of electrophiles capable of targeting K-Ras oncogenes. Biochemistry 56:3178\u20133183. https:\/\/doi.org\/10.1021\/acs.biochem.7b00271","journal-title":"Biochemistry"},{"key":"371_CR26","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.1158\/0008-5472.CAN-11-2612","volume":"72","author":"IA Prior","year":"2012","unstructured":"Prior IA, Lewis PD, Mattos C (2012) A comprehensive survey of ras mutations in cancer. Cancer Res 72:2457\u20132467. https:\/\/doi.org\/10.1158\/0008-5472.CAN-11-2612","journal-title":"Cancer Res"},{"key":"371_CR27","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/nature12796","volume":"503","author":"JM Ostrem","year":"2013","unstructured":"Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548\u2013551. https:\/\/doi.org\/10.1038\/nature12796","journal-title":"Nature"},{"key":"371_CR28","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1021\/acs.jcim.7b00399","volume":"58","author":"CI Nnadi","year":"2018","unstructured":"Nnadi CI, Jenkins ML, Gentile DR, Bateman LA, Zaidman D, Balius TE, Nomura DK, Burke JE, Shokat KM, London N (2018) Novel K-Ras G12C switch-II covalent binders destabilize Ras and accelerate nucleotide exchange. J Chem Inf Model 58:464\u2013471. https:\/\/doi.org\/10.1021\/acs.jcim.7b00399","journal-title":"J Chem Inf Model"},{"key":"371_CR29","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1158\/2159-8290.CD-15-1105","volume":"6","author":"MP Patricelli","year":"2016","unstructured":"Patricelli MP, Janes MR, Li L-S, Hansen R, Peters U, Kessler LV, Chen Y, Kucharski JM, Feng J, Ely T, Chen JH, Firdaus SJ, Babbar A, Ren P, Liu Y (2016) Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:316\u2013329. https:\/\/doi.org\/10.1158\/2159-8290.CD-15-1105","journal-title":"Cancer Discov"},{"key":"371_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1046\/j.1365-2958.2003.03289.x","volume":"47","author":"A El Zoeiby","year":"2002","unstructured":"El Zoeiby A, Sanschagrin F, Levesque RC (2002) Structure and function of the Mur enzymes: development of novel inhibitors. Mol Microbiol 47:1\u201312. https:\/\/doi.org\/10.1046\/j.1365-2958.2003.03289.x","journal-title":"Mol Microbiol"},{"key":"371_CR31","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.bioorg.2014.03.008","volume":"55","author":"M Hrast","year":"2014","unstructured":"Hrast M, Sosi\u010d I, \u0160ink R, Gobec S (2014) Inhibitors of the peptidoglycan biosynthesis enzymes MurA-F. Bioorg Chem 55:2\u201315. https:\/\/doi.org\/10.1016\/j.bioorg.2014.03.008","journal-title":"Bioorg Chem"},{"key":"371_CR32","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/978-1-4614-1400-1_2","volume-title":"Antibiotic discovery and development","author":"LL Silver","year":"2012","unstructured":"Silver LL (2012) Rational approaches to antibacterial discovery: pre-genomic directed and phenotypic screening. Antibiotic discovery and development. Springer, Boston, MA, pp 33\u201375"},{"key":"371_CR33","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/mc.22312","volume":"55","author":"B Bian","year":"2016","unstructured":"Bian B, Mongrain S, Cagnol S, Langlois M-J, Boulanger J, Bernatchez G, Carrier JC, Boudreau F, Rivard N (2016) Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis. Mol Carcinog 55:671\u2013687. https:\/\/doi.org\/10.1002\/mc.22312","journal-title":"Mol Carcinog"},{"key":"371_CR34","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.4155\/fmc.14.73","volume":"6","author":"J Kos","year":"2014","unstructured":"Kos J, Mitrovi\u0107 A, Mirkovi\u0107 B (2014) The current stage of cathepsin B inhibitors as potential anticancer agents. Future Med Chem 6:1355\u20131371. https:\/\/doi.org\/10.4155\/fmc.14.73","journal-title":"Future Med Chem"},{"key":"371_CR35","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/nrc4027","volume":"15","author":"OC Olson","year":"2015","unstructured":"Olson OC, Joyce JA (2015) Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer 15:712\u2013729. https:\/\/doi.org\/10.1038\/nrc4027","journal-title":"Nat Rev Cancer"},{"key":"371_CR36","first-page":"23","volume":"56","author":"H Ruan","year":"2015","unstructured":"Ruan H, Hao S, Young P, Zhang H (2015) Targeting cathepsin B for cancer therapies. Horizons Cancer Res 56:23\u201340","journal-title":"Horizons Cancer Res"},{"key":"371_CR37","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/0014-5793(91)80318-w","volume":"280","author":"M Murata","year":"1991","unstructured":"Murata M, Miyashita S, Yokoo C, Tamai M, Hanada K, Hatayama K, Towatari T, Nikawa T, Katunuma N (1991) Novel epoxysuccinyl peptides selective inhibitors of cathepsin B, in vitro. FEBS Lett 280:307\u2013310. https:\/\/doi.org\/10.1016\/0014-5793(91)80318-w","journal-title":"FEBS Lett"},{"key":"371_CR38","doi-asserted-by":"publisher","first-page":"387","DOI":"10.2174\/138161207780162962","volume":"13","author":"O Vasiljeva","year":"2007","unstructured":"Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B (2007) Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des 13:387\u2013403. https:\/\/doi.org\/10.2174\/138161207780162962","journal-title":"Curr Pharm Des"},{"key":"371_CR39","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1002\/cmdc.201100098","volume":"6","author":"B Mirkovi\u0107","year":"2011","unstructured":"Mirkovi\u0107 B, Renko M, Turk S, Sosi\u010d I, Jevnikar Z, Obermajer N, Turk D, Gobec S, Kos J (2011) Novel Mechanism of cathepsin B inhibition by antibiotic nitroxoline and related compounds. ChemMedChem 6:1351\u20131356. https:\/\/doi.org\/10.1002\/cmdc.201100098","journal-title":"ChemMedChem"},{"key":"371_CR40","doi-asserted-by":"publisher","first-page":"2309","DOI":"10.2174\/092986706777935122","volume":"13","author":"S Gobec","year":"2006","unstructured":"Gobec S, Frlan R (2006) Inhibitors of cathepsin B. Curr Med Chem 13:2309\u20132327. https:\/\/doi.org\/10.2174\/092986706777935122","journal-title":"Curr Med Chem"},{"key":"371_CR41","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1042\/bj2010189","volume":"201","author":"AJ Barrett","year":"1982","unstructured":"Barrett AJ, Kembhavi AA, Brown MA, Kirschke H, Knight CG, Tamai M, Hanada K (1982) l-Trans-epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L. Biochem J 201:189\u2013198. https:\/\/doi.org\/10.1042\/bj2010189","journal-title":"Biochem J"},{"key":"371_CR42","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1110\/ps.037341.108","volume":"17","author":"P Schenker","year":"2008","unstructured":"Schenker P, Alfarano P, Kolb P, Caflisch A, Baici A (2008) A Double-headed cathepsin B inhibitor devoid of warhead. Protein Sci 17:2145\u20132155. https:\/\/doi.org\/10.1110\/ps.037341.108","journal-title":"Protein Sci"},{"key":"371_CR43","doi-asserted-by":"publisher","first-page":"8951","DOI":"10.1021\/jacs.9b02822","volume":"141","author":"E Resnick","year":"2019","unstructured":"Resnick E, Bradley A, Gan J, Douangamath A, Krojer T, Sethi R, Geurink PP, Aimon A, Amitai G, Bellini D, Bennett J, Fairhead M, Fedorov O, Gabizon R, Gan J, Guo J, Plotnikov A, Reznik N, Ruda GF, D\u00edaz-S\u00e1ez L, Straub VM, Szommer T, Velupillai S, Zaidman D, Zhang Y, Coker AR, Dowson CG, Barr HM, Wang C, Huber KVM, Brennan PE, Ovaa H, Von Delft F, London N (2019) Rapid covalent-probe discovery by electrophile-fragment screening. J Am Chem Soc 141:8951\u20138968. https:\/\/doi.org\/10.1021\/jacs.9b02822","journal-title":"J Am Chem Soc"},{"key":"371_CR44","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.1074\/jbc.M109.074971","volume":"285","author":"S Li","year":"2010","unstructured":"Li S, Zheng H, Mao A-P, Zhong B, Li Y, Liu Y, Gao Y, Ran Y, Tien P, Shu H-B (2010) Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. J Biol Chem 285:4291\u20134297. https:\/\/doi.org\/10.1074\/jbc.M109.074971","journal-title":"J Biol Chem"},{"key":"371_CR45","doi-asserted-by":"publisher","first-page":"3233","DOI":"10.1093\/hmg\/ddq232","volume":"19","author":"LC Kudo","year":"2010","unstructured":"Kudo LC, Parfenova L, Vi N, Lau K, Pomakian J, Valdmanis P, Rouleau GA, Vinters HV, Wiedau-Pazos M, Karsten SL (2010) Integrative gene-tissue microarray-based approach for identification of human disease biomarkers: application to amyotrophic lateral sclerosis. Hum Mol Genet 19:3233\u20133253. https:\/\/doi.org\/10.1093\/hmg\/ddq232","journal-title":"Hum Mol Genet"},{"key":"371_CR46","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1007\/s00125-013-2889-x","volume":"56","author":"A Beck","year":"2013","unstructured":"Beck A, Vinik Y, Shatz-Azoulay H, Isaac R, Streim S, Jona G, Boura-Halfon S, Zick Y (2013) Otubain 2 is a novel promoter of beta cell survival as revealed by SiRNA high-throughput screens of human pancreatic islets. Diabetologia 56:1317\u20131326. https:\/\/doi.org\/10.1007\/s00125-013-2889-x","journal-title":"Diabetologia"},{"key":"371_CR47","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1042\/0264-6021:3570033","volume":"357","author":"L Gasmi","year":"2001","unstructured":"Gasmi L, McLennan AG (2001) The mouse Nudt7 gene encodes a peroxisomal nudix hydrolase specific for coenzyme A and its derivatives. Biochem J 357:33\u201338. https:\/\/doi.org\/10.1042\/0264-6021:3570033","journal-title":"Biochem J"},{"key":"371_CR48","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s00018-005-5386-7","volume":"63","author":"AG McLennan","year":"2006","unstructured":"McLennan AG (2006) The nudix hydrolase superfamily. Cell Mol Life Sci C 63:123\u2013143. https:\/\/doi.org\/10.1007\/s00018-005-5386-7","journal-title":"Cell Mol Life Sci C"},{"key":"371_CR49","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1042\/BST20140156","volume":"42","author":"S Jackowski","year":"2014","unstructured":"Jackowski S, Leonardi R (2014) Deregulated coenzyme A, loss of metabolic flexibility and diabetes. Biochem Soc Trans 42:1118\u20131122. https:\/\/doi.org\/10.1042\/BST20140156","journal-title":"Biochem Soc Trans"},{"key":"371_CR50","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.2174\/0929867043364775","volume":"11","author":"P Riederer","year":"2004","unstructured":"Riederer P, Lachenmayer L, Laux G (2004) Clinical applications of MAO-inhibitors. Curr Med Chem 11:2033\u20132043. https:\/\/doi.org\/10.2174\/0929867043364775","journal-title":"Curr Med Chem"},{"key":"371_CR51","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.2174\/1568026611212200011","volume":"12","author":"M Yanez","year":"2013","unstructured":"Yanez M, Fernando Padin J, Alberto Arranz-Tagarro J, Camina M, Laguna R (2013) History and therapeutic use of MAO-A inhibitors: a historical perspective of MAO-A inhibitors as antidepressant drug. Curr Top Med Chem 12:2275\u20132282. https:\/\/doi.org\/10.2174\/1568026611212200011","journal-title":"Curr Top Med Chem"},{"key":"371_CR52","doi-asserted-by":"publisher","first-page":"340","DOI":"10.3389\/fphar.2016.00340","volume":"7","author":"JPM Finberg","year":"2016","unstructured":"Finberg JPM, Rabey JM (2016) Inhibitors of MAO-A and MAO-B in psychiatry and neurology. Front Pharmacol 7:340. https:\/\/doi.org\/10.3389\/fphar.2016.00340","journal-title":"Front Pharmacol"},{"key":"371_CR53","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1016\/0006-2952(68)90066-X","volume":"17","author":"JP Johnston","year":"1968","unstructured":"Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17:1285\u20131297. https:\/\/doi.org\/10.1016\/0006-2952(68)90066-X","journal-title":"Biochem Pharmacol"},{"key":"371_CR54","volume-title":"Schr\u00f6dinger release 2019-4: LigPrep","author":"Schr\u00f6dinger Inc","year":"2019","unstructured":"Schr\u00f6dinger Inc (2019) Schr\u00f6dinger release 2019-4: LigPrep. Schr\u00f6dinger Inc, New York, NY"},{"key":"371_CR55","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","volume":"28","author":"HM Berman","year":"2000","unstructured":"Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235\u2013242. https:\/\/doi.org\/10.1093\/nar\/28.1.235","journal-title":"Nucleic Acids Res"},{"key":"371_CR56","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1016\/S0969-2126(96)00153-0","volume":"4","author":"T Skarzynski","year":"1996","unstructured":"Skarzynski T, Mistry A, Wonacott A, Hutchinson SE, Kelly VA, Duncan K (1996) Structure of UDP-N-acetylglucosamine enolpyruvyl transferase, an enzyme essential for the synthesis of bacterial peptidoglycan, complexed with substrate UDP-N-acetylglucosamine and the drug fosfomycin. Structure 4:1465\u20131474. https:\/\/doi.org\/10.1016\/S0969-2126(96)00153-0","journal-title":"Structure"},{"key":"371_CR57","doi-asserted-by":"publisher","first-page":"4276","DOI":"10.1021\/bi100365b","volume":"49","author":"H Han","year":"2010","unstructured":"Han H, Yang Y, Olesen SH, Becker A, Betzi S, Sch\u00f6nbrunn E (2010) The fungal product terreic acid is a covalent inhibitor of the bacterial cell wall biosynthetic enzyme UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA). Biochemistry 49:4276\u20134282. https:\/\/doi.org\/10.1021\/bi100365b","journal-title":"Biochemistry"},{"key":"371_CR58","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1021\/acs.jmedchem.7b01430","volume":"61","author":"B Wei","year":"2018","unstructured":"Wei B, Gunzner-Toste J, Yao H, Wang T, Wang J, Xu Z, Chen J, Wai J, Nonomiya J, Tsai SP, Chuh J, Kozak KR, Liu Y, Yu S-F, Lau J, Li G, Phillips GD, Leipold D, Kamath A, Su D, Xu K, Eigenbrot C, Steinbacher S, Ohri R, Raab H, Staben LR, Zhao G, Flygare JA, Pillow TH, Verma V, Masterson LA, Howard PW, Safina B (2018) Discovery of peptidomimetic antibody-drug conjugate linkers with enhanced protease specificity. J Med Chem 61:989\u20131000. https:\/\/doi.org\/10.1021\/acs.jmedchem.7b01430","journal-title":"J Med Chem"},{"key":"371_CR59","doi-asserted-by":"publisher","first-page":"12684","DOI":"10.1073\/pnas.0505975102","volume":"102","author":"L De Colibus","year":"2005","unstructured":"De Colibus L, Li M, Binda C, Lustig A, Edmondson DE, Mattevi A (2005) Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B. Proc Natl Acad Sci 102:12684\u201312689. https:\/\/doi.org\/10.1073\/pnas.0505975102","journal-title":"Proc Natl Acad Sci"},{"key":"371_CR60","volume-title":"Schr\u00f6dinger release 2019-4: protein preparation wizard","author":"Schr\u00f6dinger Inc","year":"2019","unstructured":"Schr\u00f6dinger Inc (2019) Schr\u00f6dinger release 2019-4: Protein Preparation Wizard. Schr\u00f6dinger Inc, New York, NY"},{"key":"371_CR61","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"G Madhavi Sastry","year":"2013","unstructured":"Madhavi Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221\u2013234. https:\/\/doi.org\/10.1007\/s10822-013-9644-8","journal-title":"J Comput Aided Mol Des"},{"key":"371_CR62","volume-title":"Schr\u00f6dinger release (2019-4): QSite","author":"Schr\u00f6dinger Inc","year":"2019","unstructured":"Schr\u00f6dinger Inc (2019) Schr\u00f6dinger release (2019-4): QSite. Schr\u00f6dinger Inc, New York, NY"},{"key":"371_CR63","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1002\/(SICI)1096-987X(19991115)20:14<1468::AID-JCC2>3.0.CO;2-0","volume":"20","author":"DM Philipp","year":"1999","unstructured":"Philipp DM, Friesner RA (1999) Mixed ab initio QM\/MM modeling using frozen orbitals and tests with alanine dipeptide and tetrapeptide. J Comput Chem 20:1468\u20131494. https:\/\/doi.org\/10.1002\/(SICI)1096-987X(19991115)20:14%3c1468::AID-JCC2%3e3.0.CO;2-0","journal-title":"J Comput Chem"},{"key":"371_CR64","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1002\/1096-987X(200012)21:16<1442::AID-JCC3>3.0.CO;2-O","volume":"21","author":"RB Murphy","year":"2000","unstructured":"Murphy RB, Philipp DM, Friesner RA (2000) A mixed quantum mechanics\/molecular mechanics (QM\/MM) method for large-scale modeling of chemistry in protein environments. J Comput Chem 21:1442\u20131457. https:\/\/doi.org\/10.1002\/1096-987X(200012)21:16%3c1442::AID-JCC3%3e3.0.CO;2-O","journal-title":"J Comput Chem"},{"key":"371_CR65","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1093\/bioinformatics\/btx181","volume":"33","author":"I Soylu","year":"2017","unstructured":"Soylu I, Marino SM (2017) Cpipe: a comprehensive computational platform for sequence and structure-based analyses of cysteine residues. Bioinformatics 33:2395\u20132396. https:\/\/doi.org\/10.1093\/bioinformatics\/btx181","journal-title":"Bioinformatics"},{"key":"371_CR66","doi-asserted-by":"publisher","first-page":"3364","DOI":"10.1093\/nar\/gkg601","volume":"31","author":"L Cavallo","year":"2003","unstructured":"Cavallo L, Kleinjung J, Fraternali F (2003) POPS: a fast algorithm for solvent accessible surface areas at atomic and residue level. Nucleic Acids Res 31:3364\u20133366. https:\/\/doi.org\/10.1093\/nar\/gkg601","journal-title":"Nucleic Acids Res"},{"key":"371_CR67","doi-asserted-by":"publisher","first-page":"9171","DOI":"10.1021\/acs.jmedchem.5b01018","volume":"58","author":"VJ Cee","year":"2015","unstructured":"Cee VJ, Volak LP, Chen Y, Bartberger MD, Tegley C, Arvedson T, McCarter J, Tasker AS, Fotsch C (2015) Systematic study of the glutathione (GSH) reactivity of N-arylacrylamides: 1. Effects of aryl substitution. J Med Chem 58:9171\u20139178. https:\/\/doi.org\/10.1021\/acs.jmedchem.5b01018","journal-title":"J Med Chem"},{"key":"371_CR68","doi-asserted-by":"publisher","first-page":"3124","DOI":"10.1021\/acs.jcim.7b00553","volume":"57","author":"R Lonsdale","year":"2017","unstructured":"Lonsdale R, Burgess J, Colclough N, Davies NL, Lenz EM, Orton AL, Ward RA (2017) Expanding the armory: predicting and tuning covalent warhead reactivity. J Chem Inf Model 57:3124\u20133137. https:\/\/doi.org\/10.1021\/acs.jcim.7b00553","journal-title":"J Chem Inf Model"},{"key":"371_CR69","doi-asserted-by":"publisher","first-page":"10072","DOI":"10.1021\/jm501412a","volume":"57","author":"ME Flanagan","year":"2014","unstructured":"Flanagan ME, Abramite JA, Anderson DP, Aulabaugh A, Dahal UP, Gilbert AM, Li C, Montgomery J, Oppenheimer SR, Ryder T, Schuff BP, Uccello DP, Walker GS, Wu Y, Brown MF, Chen JM, Hayward MM, Noe MC, Obach RS, Philippe L, Shanmugasundaram V, Shapiro MJ, Starr J, Stroh J, Che Y (2014) Chemical and computational methods for the characterization of covalent reactive groups for the prospective design of irreversible inhibitors. J Med Chem 57:10072\u201310079. https:\/\/doi.org\/10.1021\/jm501412a","journal-title":"J Med Chem"},{"key":"371_CR70","volume-title":"Gaussian 09","author":"MJ Frisch","year":"2009","unstructured":"Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA (2009) Gaussian 09. Gaussian Inc, Wallingford"},{"key":"371_CR71","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1007\/s00214-007-0310-x","volume":"120","author":"Y Zhao","year":"2008","unstructured":"Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other function. Theor Chem Acc 120:215\u2013241. https:\/\/doi.org\/10.1007\/s00214-007-0310-x","journal-title":"Theor Chem Acc"},{"key":"371_CR72","doi-asserted-by":"publisher","first-page":"4279","DOI":"10.1021\/ol701872z","volume":"9","author":"TA Rokob","year":"2007","unstructured":"Rokob TA, Hamza A, P\u00e1pai I (2007) Computing reliable energetics for conjugate addition reactions. Org Lett 9:4279\u20134282. https:\/\/doi.org\/10.1021\/ol701872z","journal-title":"Org Lett"},{"key":"371_CR73","doi-asserted-by":"publisher","first-page":"6670","DOI":"10.1039\/c0cp02984j","volume":"13","author":"L Goerigk","year":"2011","unstructured":"Goerigk L, Grimme S (2011) A thorough benchmark of density functional methods for general main group thermochemistry, kinetics, and noncovalent interactions. Phys Chem Chem Phys 13:6670. https:\/\/doi.org\/10.1039\/c0cp02984j","journal-title":"Phys Chem Chem Phys"},{"key":"371_CR74","doi-asserted-by":"publisher","first-page":"10455","DOI":"10.1021\/jm501501a","volume":"57","author":"OM Bautista-Aguilera","year":"2014","unstructured":"Bautista-Aguilera OM, Samadi A, Chioua M, Nikolic K, Filipic S, Agbaba D, Soriano E, de Andr\u00e9s L, Rodr\u00edguez-Franco MI, Alcaro S, Ramsay RR, Ortuso F, Ya\u00f1ez M, Marco-Contelles J (2014) N-Methyl-N-((1-methyl-5-(3-(1-(2-Methylbenzyl)piperidin-4-Yl)propoxy)-1H-indol-2-Yl)methyl)prop-2-Yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor. J Med Chem 57:10455\u201310463. https:\/\/doi.org\/10.1021\/jm501501a","journal-title":"J Med Chem"},{"key":"371_CR75","unstructured":"von der Eltz H, Guder H-J, Muehlegger K (1990) New hydrolase substrates. US4900822a"},{"key":"371_CR76","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1021\/acs.jcim.8b00454","volume":"58","author":"E Awoonor-Williams","year":"2018","unstructured":"Awoonor-Williams E, Rowley CN (2018) How reactive are druggable cysteines in protein kinases? J Chem Inf Model 58:1935\u20131946. https:\/\/doi.org\/10.1021\/acs.jcim.8b00454","journal-title":"J Chem Inf Model"},{"key":"371_CR77","doi-asserted-by":"publisher","first-page":"4995","DOI":"10.1111\/febs.14994","volume":"284","author":"ML Di Paolo","year":"2019","unstructured":"Di Paolo ML, Cozza G, Milelli A, Zonta F, Sarno S, Minniti E, Ursini F, Rosini M, Minarini A (2019) Benextramine and derivatives as novel human monoamine oxidases inhibitors: an integrated approach. FEBS J 284:4995\u20135015. https:\/\/doi.org\/10.1111\/febs.14994","journal-title":"FEBS J"}],"container-title":["Journal of Computer-Aided Molecular Design"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-020-00371-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10822-020-00371-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-020-00371-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T07:28:20Z","timestamp":1614151700000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10822-020-00371-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,18]]},"references-count":77,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["371"],"URL":"https:\/\/doi.org\/10.1007\/s10822-020-00371-5","relation":{},"ISSN":["0920-654X","1573-4951"],"issn-type":[{"value":"0920-654X","type":"print"},{"value":"1573-4951","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,18]]},"assertion":[{"value":"18 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}