title: Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study.
abstract: Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CL(pro) provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.
authors.affiliation: South African Medical Research Council Bioinformatics Capacity Development Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville 7535, South Africa. michael@sanbi.ac.za.|Molecular Biology and Virology Laboratory, Department of Medical BioSciences, Faculty of Natural Sciences, University of the Western Cape, Western Cape, Bellville 7535, South Africa. michael@sanbi.ac.za.
authors.forename: Michael
authors.initials: M
authors.lastname: Berry
authors.affiliation: Molecular Biology and Virology Laboratory, Department of Medical BioSciences, Faculty of Natural Sciences, University of the Western Cape, Western Cape, Bellville 7535, South Africa. bfielding@uwc.ac.za.
authors.forename: Burtram C
authors.initials: BC
authors.lastname: Fielding
authors.affiliation: South African Medical Research Council Bioinformatics Capacity Development Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville 7535, South Africa. junaid@sanbi.ac.za.
authors.forename: Junaid
authors.initials: J
authors.lastname: Gamieldien
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D017934:Coronavirus / Q000187:drug effects*; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases
keywords: 3CLpro; human coronaviruses; molecular docking; molecular dynamics; structure-based drug design; virtual screening