Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study

Viruses

Michael Berry²  Burtram C. Fielding¹  Junaid Gamieldien² 

[1] Molecular Biology and Virology Laboratory, Department of Medical BioSciences, Faculty of Natural Sciences, University of the Western Cape, Western Cape, Bellville 7535, South AfricaSouth African Medical Research Council Bioinformatics Capacity Development Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville 7535, South Africa;

关键词: human coronaviruses;    molecular docking;    3CL^pro;    virtual screening;    structure-based drug design;    molecular dynamics;   

DOI  :  10.3390/v7122963

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.