Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules. Issue 48 (30th November 2021)

• Record Type: Journal Article
• Authors: Gentile, Francesco; Fernandez, Michael; Ban, Fuqiang; Ton, Anh-Tien; Mslati, Hazem; Perez, Carl F.; Leblanc, Eric; Yaacoub, Jean Charle; Gleave, James; Stern, Abraham; Wong, Bill; Jean, François; Strynadka, Natalie; Cherkasov, Artem
• Is Part Of: Chemical science. Volume 12:Issue 48(2021)
• Page Start: 15960
• Page End: 15974
• Publication Date: 2021-11-30
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc05579h
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Deep learning-accelerated docking coupled with computational hit selection strategies enable the identification of inhibitors for the SARS-CoV-2 main protease from a chemical library of 40 billion small molecules. Abstract : Recent explosive growth of 'make-on-demand' chemical libraries brought unprecedented opportunities but also significant challenges to the field of computer-aided drug discovery. To address this expansion of the accessible chemical universe, molecular docking needs to accurately rank billions of chemical structures, calling for the development of automated hit-selecting protocols to minimize human intervention and error. Herein, we report the development of an artificial intelligence-driven virtual screening pipeline that utilizes Deep Docking with Autodock GPU, Glide SP, FRED, ICM and QuickVina2 programs to screen 40 billion molecules against SARS-CoV-2 main protease (Mpro). This campaign returned a significant number of experimentally confirmed inhibitors of Mpro enzyme, and also enabled to benchmark the performance of twenty-eight hit-selecting strategies of various degrees of stringency and automation. These findings provide new starting scaffolds for hit-to-lead optimization campaigns against Mpro and encourage the development of fully automated end-to-end drug discovery protocols integrating machine learning and human expertise.