{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:18:25Z","timestamp":1790864305130,"version":"4.1.0"},"reference-count":84,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T00:00:00Z","timestamp":1634256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"publisher","award":["P2-0046"],"award-info":[{"award-number":["P2-0046"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"publisher","award":["J1-1715"],"award-info":[{"award-number":["J1-1715"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"publisher","award":["J1-9186"],"award-info":[{"award-number":["J1-9186"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"publisher","award":["J1-2471"],"award-info":[{"award-number":["J1-2471"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005989","name":"Ministry of Education, Science and Sport","doi-asserted-by":"publisher","award":["OP20.04342"],"award-info":[{"award-number":["OP20.04342"]}],"id":[{"id":"10.13039\/501100005989","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005989","name":"Ministry of Education, Science and Sport","doi-asserted-by":"publisher","award":["HPC-RIVR"],"award-info":[{"award-number":["HPC-RIVR"]}],"id":[{"id":"10.13039\/501100005989","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new pathogen from the family of Coronaviridae that caused a global pandemic of COVID-19 disease. In the absence of effective antiviral drugs, research of novel therapeutic targets such as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) becomes essential. This viral protein is without a human counterpart and thus represents a unique prospective drug target. However, in vitro biological evaluation testing on RdRp remains difficult and is not widely available. Therefore, we prepared a database of commercial small-molecule compounds and performed an in silico high-throughput virtual screening on the active site of the SARS-CoV-2 RdRp using ensemble docking. We identified a novel thioether-amide or guanidine-linker class of potential RdRp inhibitors and calculated favorable binding free energies of representative hits by molecular dynamics simulations coupled with Linear Interaction Energy calculations. This innovative procedure maximized the respective phase-space sampling and yielded non-covalent inhibitors representing small optimizable molecules that are synthetically readily accessible, commercially available as well as suitable for further biological evaluation and mode of action studies.<\/jats:p>","DOI":"10.3390\/ijms222011143","type":"journal-article","created":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T13:45:17Z","timestamp":1634564717000},"page":"11143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Potential Novel Thioether-Amide or Guanidine-Linker Class of SARS-CoV-2 Virus RNA-Dependent RNA Polymerase Inhibitors Identified by High-Throughput Virtual Screening Coupled to Free-Energy Calculations"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6083-5024","authenticated-orcid":false,"given":"Marko","family":"Juki\u010d","sequence":"first","affiliation":[{"name":"Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia"},{"name":"Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagolja\u0161ka 8, SI-6000 Koper, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4067-0116","authenticated-orcid":false,"given":"Du\u0161anka","family":"Jane\u017ei\u010d","sequence":"additional","affiliation":[{"name":"Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagolja\u0161ka 8, SI-6000 Koper, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urban","family":"Bren","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia"},{"name":"Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagolja\u0161ka 8, SI-6000 Koper, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/s41564-020-0695-z","article-title":"Coronaviridae Study Group of the International Committee on Taxonomy of Viruses The Species Severe Acute Respiratory Syndrome-Related Coronavirus: Classifying 2019-NCoV and Naming It SARS-CoV-2","volume":"5","author":"Gorbalenya","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A Novel Coronavirus from Patients with Pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and Evolution of Pathogenic Coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nrmicro.2016.81","article-title":"SARS and MERS: Recent Insights into Emerging Coronaviruses","volume":"14","author":"Falzarano","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.antiviral.2013.08.015","article-title":"From SARS to MERS: 10 Years of Research on Highly Pathogenic Human Coronaviruses","volume":"100","author":"Hilgenfeld","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.tim.2015.06.003","article-title":"Bat-to-Human: Spike Features Determining \u2018Host Jump\u2019 of Coronaviruses SARS-CoV, MERS-CoV, and Beyond","volume":"23","author":"Lu","year":"2015","journal-title":"Trends Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A New Coronavirus Associated with Human Respiratory Disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1056\/NEJMoa2001316","article-title":"Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus\u2013Infected Pneumonia","volume":"382","author":"Li","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.ijid.2020.01.009","article-title":"The Continuing 2019-NCoV Epidemic Threat of Novel Coronaviruses to Global Health\u2014The Latest 2019 Novel Coronavirus Outbreak in Wuhan, China","volume":"91","author":"Hui","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0140-6736(20)30185-9","article-title":"A Novel Coronavirus Outbreak of Global Health Concern","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_11","unstructured":"Johns Hopkins University (2021, October 09). Mortality Analyses. Available online: https:\/\/coronavirus.jhu.edu\/data\/mortality."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/s41586-020-2918-0","article-title":"Age-Specific Mortality and Immunity Patterns of SARS-CoV-2","volume":"590","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.jcrc.2020.03.005","article-title":"A Systematic Review on the Efficacy and Safety of Chloroquine for the Treatment of COVID-19","volume":"57","author":"Cortegiani","year":"2020","journal-title":"J. Crit. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"72","DOI":"10.5582\/bst.2020.01047","article-title":"Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies","volume":"14","author":"Gao","year":"2020","journal-title":"Biosci. Trends"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/cid\/ciaa237","article-title":"In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)","volume":"71","author":"Yao","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105949","DOI":"10.1016\/j.ijantimicag.2020.105949","article-title":"Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial","volume":"56","author":"Gautret","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41422-020-0282-0","article-title":"Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-NCoV) In Vitro","volume":"30","author":"Wang","year":"2020","journal-title":"Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00221-18","DOI":"10.1128\/mBio.00221-18","article-title":"Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease","volume":"9","author":"Agostini","year":"2018","journal-title":"mBio"},{"key":"ref_19","unstructured":"Ren, X., Shao, X.X., Li, X.X., Jia, X.H., Song, T., Zhou, W.Y., Wang, P., Li, Y., Wang, X.L., and Cui, Q.H. (2021, October 09). Identifying Potential Treatments Using a Data-Driven Approach. Available online: https:\/\/blog.drugbankplus.com\/data-driven-approaches-to-identify-potential-covid-19-therapies\/?li=DB-home\/Covid-1\/1."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/d41573-020-00016-0","article-title":"Therapeutic Options for the 2019 Novel Coronavirus (2019-NCoV)","volume":"19","author":"Li","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41421-020-0153-3","article-title":"Network-Based Drug Repurposing for Novel Coronavirus 2019-NCoV\/SARS-CoV-2","volume":"6","author":"Zhou","year":"2020","journal-title":"Cell Discov."},{"key":"ref_23","unstructured":"Jazzi, A.S., Mahnam, K., Hejazi, S.H., Damavandi, M.S., Sadeghi, P., Zeinalian, M., and Khanahmad, H. (2020). Inhibition of Viral Macrodomain of COVID-19 and Human TRPM2 by losartan. Preprints, 2020030457."},{"key":"ref_24","unstructured":"Dahly, D., Gates, S., and Morris, T. (2020). Statistical review of hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label nonrandomized clinical trial. Zenodo."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1002\/jmv.26165","article-title":"Can Steroids Reverse the Severe COVID-19 Induced \u201cCytokine Storm\u201d?","volume":"92","author":"Kolilekas","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10970","DOI":"10.1073\/pnas.2005615117","article-title":"Effective Treatment of Severe COVID-19 Patients with Tocilizumab","volume":"117","author":"Xu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102523","DOI":"10.1016\/j.autrev.2020.102523","article-title":"COVID-19 Infection and Rheumatoid Arthritis: Faraway, so Close!","volume":"19","author":"Favalli","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1007\/s10067-020-05073-9","article-title":"Rheumatologists\u2019 Perspective on Coronavirus Disease 19 (COVID-19) and Potential Therapeutic Targets","volume":"39","author":"Misra","year":"2020","journal-title":"Clin. Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mehra, M.R., Desai, S.S., Ruschitzka, F., and Patel, A.N. (2020). RETRACTED: Hydroxychloroquine or Chloroquine with or without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis. Lancet, in press.","DOI":"10.1016\/S0140-6736(20)31180-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117477","DOI":"10.1016\/j.lfs.2020.117477","article-title":"Anti-HCV, Nucleotide Inhibitors, Repurposing against COVID-19","volume":"248","author":"Elfiky","year":"2020","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chang, Y.-C., Tung, Y.-A., Lee, K.-H., Chen, T.-F., Hsiao, Y.-C., Chang, H.-C., Hsieh, T.-T., Su, C.-H., Wang, S.-S., and Yu, J.-Y. (2020, February 29). Potential Therapeutic Agents for COVID-19 Based on the Analysis of Protease and RNA Polymerase Docking. Available online: https:\/\/www.preprints.org\/manuscript\/202002.0242\/v1.","DOI":"10.20944\/preprints202002.0242.v1"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4933","DOI":"10.1038\/sj.emboj.7601368","article-title":"A Second, Non-Canonical RNA-Dependent RNA Polymerase in SARS Coronavirus","volume":"25","author":"Imbert","year":"2006","journal-title":"EMBO J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.virol.2005.02.017","article-title":"Expression, Purification, and Characterization of SARS Coronavirus RNA Polymerase","volume":"335","author":"Cheng","year":"2005","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Romano, M., Ruggiero, A., Squeglia, F., Maga, G., and Berisio, R. (2020). A Structural View of SARS-CoV-2 RNA Replication Machinery: RNA Synthesis, Proofreading and Final Capping. Cells, 9.","DOI":"10.20944\/preprints202004.0510.v1"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e01508-20","DOI":"10.1128\/AAC.01508-20","article-title":"Development of a Simple In Vitro Assay To Identify and Evaluate Nucleotide Analogs against SARS-CoV-2 RNA-Dependent RNA Polymerase","volume":"65","author":"Lu","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1002\/jmv.26264","article-title":"RNA-dependent RNA Polymerase of SARS-CoV-2 as a Therapeutic Target","volume":"93","author":"Wang","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_37","first-page":"3204","article-title":"SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp) Targeting: An in Silico Perspective","volume":"39","author":"Elfiky","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1038\/s41467-019-10280-3","article-title":"Structure of the SARS-CoV Nsp12 Polymerase Bound to Nsp7 and Nsp8 Co-Factors","volume":"10","author":"Kirchdoerfer","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/S0959-440X(98)80089-4","article-title":"The Mechanism of Action of T7 DNA Polymerase","volume":"8","author":"Ellenberger","year":"1998","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1080\/1062936X.2018.1454981","article-title":"Molecular Docking Revealed the Binding of Nucleotide\/Side Inhibitors to Zika Viral Polymerase Solved Structures","volume":"29","author":"Elfiky","year":"2018","journal-title":"SAR QSAR Environ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1093\/bioinformatics\/btm404","article-title":"Clustal W and Clustal X Version 2.0","volume":"23","author":"Larkin","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1126\/science.abb7498","article-title":"Structure of the RNA-Dependent RNA Polymerase from COVID-19 Virus","volume":"368","author":"Gao","year":"2020","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41467-020-20542-0","article-title":"Mechanism of SARS-CoV-2 Polymerase Stalling by Remdesivir","volume":"12","author":"Kokic","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1126\/science.abc1560","article-title":"Structural Basis for Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir","volume":"368","author":"Yin","year":"2020","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"130","DOI":"10.2174\/1573406414666181015152511","article-title":"Novel Guanosine Derivatives as Anti-HCV NS5b Polymerase: A QSAR and Molecular Docking Study","volume":"15","author":"Elfiky","year":"2019","journal-title":"Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/jmv.24934","article-title":"Molecular Dynamics Simulation Revealed Binding of Nucleotide Inhibitors to ZIKV Polymerase over 444 Nanoseconds","volume":"90","author":"Elfiky","year":"2018","journal-title":"J. Med. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1002\/jmv.24736","article-title":"Quantitative Structure-Activity Relationship and Molecular Docking Revealed a Potency of Anti-Hepatitis C Virus Drugs against Human Corona Viruses","volume":"89","author":"Elfiky","year":"2017","journal-title":"J. Med. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.jmb.2012.03.008","article-title":"Structure-Based Inhibition of Norovirus RNA-Dependent RNA Polymerases","volume":"419","author":"Mastrangelo","year":"2012","journal-title":"J. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.3390\/v2102169","article-title":"Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B","volume":"2","author":"Powdrill","year":"2010","journal-title":"Viruses"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9294","DOI":"10.1038\/s41598-020-66440-9","article-title":"Sofosbuvir as a Potential Alternative to Treat the SARS-CoV-2 Epidemic","volume":"10","author":"Becerra","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/jmv.26222","article-title":"SARS-CoV-2 and SARS-CoV: Virtual Screening of Potential Inhibitors Targeting RNA-dependent RNA Polymerase Activity (NSP12)","volume":"93","author":"Ruan","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the Treatment of Covid-19\u2014Final Report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.1074\/jbc.AC120.013056","article-title":"The Antiviral Compound Remdesivir Potently Inhibits RNA-Dependent RNA Polymerase from Middle East Respiratory Syndrome Coronavirus","volume":"295","author":"Gordon","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s15010-020-01557-7","article-title":"Remdesivir in Coronavirus Disease 2019 (COVID-19) Treatment: A Review of Evidence","volume":"49","author":"Lin","year":"2021","journal-title":"Infection"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1186\/s12967-020-02439-0","article-title":"Analysis of SARS-CoV-2 RNA-Dependent RNA Polymerase as a Potential Therapeutic Drug Target Using a Computational Approach","volume":"18","author":"Aftab","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7274","DOI":"10.1021\/jm061103g","article-title":"Interpreting Steep Dose-Response Curves in Early Inhibitor Discovery","volume":"49","author":"Shoichet","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/minf.201100076","article-title":"KNIME Workflow to Assess PAINS Filters in SMARTS Format. Comparison of RDKit and Indigo Cheminformatics Libraries","volume":"30","author":"Saubern","year":"2011","journal-title":"Mol. Inf."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","article-title":"OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins","volume":"12","author":"Harder","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/S1359-6446(97)01163-X","article-title":"Virtual Screening\u2014An Overview","volume":"3","author":"Walters","year":"1998","journal-title":"Drug Discov. Today"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6560","DOI":"10.1021\/jm301916b","article-title":"Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based on a Critical Literature Analysis: Miniperspective","volume":"56","author":"Zhu","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1107\/S0907444998009378","article-title":"Protein Data Bank (PDB): Database of Three-Dimensional Structural Information of Biological Macromolecules","volume":"54","author":"Sussman","year":"1998","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/jcc.23899","article-title":"New Ways to Boost Molecular Dynamics Simulations","volume":"36","author":"Krieger","year":"2015","journal-title":"J. Comput. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.jmgm.2006.02.009","article-title":"Fast Empirical PKa Prediction by Ewald Summation","volume":"25","author":"Krieger","year":"2006","journal-title":"J. Mol. Graph. Model."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/978-1-61779-465-0_25","article-title":"Assignment of Protonation States in Proteins and Ligands: Combining pKa Prediction with Hydrogen Bonding Network Optimization","volume":"Volume 819","author":"Baron","year":"2012","journal-title":"Computational Drug Discovery and Design"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/prot.21123","article-title":"Comparison of Multiple Amber Force Fields and Development of Improved Protein Backbone Parameters","volume":"65","author":"Hornak","year":"2006","journal-title":"Proteins"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A Smooth Particle Mesh Ewald Method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Jamroz, M., and Kolinski, A. (2013). ClusCo: Clustering and Comparison of Protein Models. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-62"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/0471250953.bi0207s02","article-title":"The InterPro Database and Tools for Protein Domain Analysis","volume":"2","author":"Mulder","year":"2003","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1093\/bioinformatics\/16.4.404","article-title":"The PSIPRED Protein Structure Prediction Server","volume":"16","author":"McGuffin","year":"2000","journal-title":"Bioinformatics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"D247","DOI":"10.1093\/nar\/gki024","article-title":"The CATH Domain Structure Database and related resources Gene3D and DHS provide comprehensive domain family information for genome analysis","volume":"33","author":"Pearl","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1126\/science.1259210","article-title":"Structural Basis for RNA Replication by the Hepatitis C Virus Polymerase","volume":"347","author":"Appleby","year":"2015","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"J\u00e1come, R., Becerra, A., Ponce de Le\u00f3n, S., and Lazcano, A. (2015). Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139001"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s10822-012-9584-8","article-title":"FRED and HYBRID Docking Performance on Standardized Datasets","volume":"26","author":"McGann","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1021\/ci100436p","article-title":"FRED Pose Prediction and Virtual Screening Accuracy","volume":"51","author":"McGann","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/bip.10207","article-title":"Gaussian Docking Functions","volume":"68","author":"McGann","year":"2003","journal-title":"Biopolymers"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1016\/j.bpj.2018.02.038","article-title":"Ensemble Docking in Drug Discovery","volume":"114","author":"Amaro","year":"2018","journal-title":"Biophys. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1093\/bioinformatics\/btl332","article-title":"THESEUS: Maximum Likelihood Superpositioning and Analysis of Macromolecular Structures","volume":"22","author":"Theobald","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/protein\/7.3.385","article-title":"A New Method for Predicting Binding Affinity in Computer-Aided Drug Design","volume":"7","author":"Medina","year":"1994","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4018","DOI":"10.1021\/acs.jcim.9b00609","article-title":"A Comparative Linear Interaction Energy and MM\/PBSA Study on SIRT1\u2013Ligand Binding Free Energy Calculation","volume":"59","author":"Rifai","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1023\/A:1007930623000","article-title":"Ligand binding affinity prediction by linear interaction energy methods","volume":"12","author":"Hansson","year":"1998","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1016\/j.bpj.2010.02.034","article-title":"Improved Ligand-Protein Binding Affinity Predictions Using Multiple Binding Modes","volume":"98","author":"Stjernschantz","year":"2010","journal-title":"Biophys. J."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Klvana, M., and Bren, U. (2019). Aflatoxin B1\u2013Formamidopyrimidine DNA Adducts: Relationships between Structures, Free Energies, and Melting Temperatures. Molecules, 24.","DOI":"10.3390\/molecules24010150"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Juki\u010d, M., Jane\u017ei\u010d, D., and Bren, U. (2020). Ensemble Docking Coupled to Linear Interaction Energy Calculations for Identification of Coronavirus Main Protease (3CLpro) Non-Covalent Small-Molecule Inhibitors. Molecules, 25.","DOI":"10.3390\/molecules25245808"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11143\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:15:40Z","timestamp":1760166940000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11143"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,15]]},"references-count":84,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222011143"],"URL":"https:\/\/doi.org\/10.3390\/ijms222011143","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,15]]}}}