Strengths and Weaknesses of Docking Simulations in the SARS-CoV-2 Era: the Main Protease (Mpro) Case Study

• DOI: 10.1021/acs.jcim.1c00404
• Publication Date: 2021-07-27T11:53:26Z
• Authors: Manuel A. Llanos; Melisa E. Gantner; Santiago Rodriguez; Lucas N. Alberca; Carolina L. Bellera; Alan Talevi; Luciana Gavernet
• Keywords: Docking (animal); Strengths and weaknesses

The scientific community is working against the clock to arrive at therapeutic interventions treat patients with COVID-19. Among strategies for drug discovery, virtual screening approaches have capacity search potential hits within millions of chemical structures in days, appropriate computing infrastructure. In this article, we first analyzed published research targeting inhibition main protease (Mpro), one most studied targets SARS-CoV-2, by docking-based methods. An alarming finding was lack an adequate validation docking protocols (i.e., pose prediction and accuracy) before applying them campaigns. performance tested some level 57.7% 168 investigations analyzed. However, found only three examples a complete retrospective analysis scoring functions quantify accuracy Moreover, two publications reported experimental evaluation proposed until preparing manuscript. All these findings led us carry out different protocols, through their accuracy. Surprisingly, that even though all good prediction, quite limited as they fail correctly rank test set compounds. These results highlight importance conducting carrying campaigns, experimentally confirm predictions made models drawing bold conclusions. Finally, successful structure-based discovery during redaction manuscript allow propose inclusion target flexibility consensus alternatives improve