Rapid Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease by Deep Docking of 1.3 Billion Compounds

Abstract

The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vaccine or a small molecule therapeutics for SARS-CoV-2. Along these efforts, the structure of SARS-CoV-2 main protease (Mpro) has been rapidly resolved and made publicly available to facilitate global efforts to develop novel drug candidates. Recently, our group has developed a novel deep learning platform -Deep Docking (DD) which provides fast prediction of docking scores of Glide (or any other docking program) and, hence, enables structure-based virtual screening of billions of purchasable molecules in a short time. In the current study we applied DD to all 1.3 billion compounds from ZINC15 library to identify top 1,000 potential ligands for SARS-CoV-2 Mpro protein. The compounds are made publicly available for further characterization and development by scientific community.

Origin, Potential Therapeutic Targets and Treatment for Coronavirus Disease (COVID-19)

“…Many of these molecules can be evaluated in wet labs in the near future [105]. ACE2 blockers can be another option to avoid the infection [106]. Similarly, there are some molecules including GSK1838705A, KT203, KT185, and BMS195614 that have strong binding affinities with RBD of the viral S-protein [107].…”

“…The interventions into the ACE2 binding abilities of SARS-CoV-2 and similar viruses, by the inhibition of the corresponding serine protease [106], can be an area of investigation. Easy, highly reliable, and early-stage diagnosis procedures are still required as a challenge for biomedical researchers [52,53].…”

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

“…Despite the structural differences in the active sites of both Mpro proteins, major issues involving plasticity and flexibility of the binding site could result in significant difficulties in inhibitor design for this molecular target. Indeed, an in silico attempt has already been made involving a massive virtual screening for Mpro inhibitors of SARS-CoV-2 using Deep Docking [15]. Other recent attempts focused on virtual screening for putative inhibitors of the same main protease of SARS-CoV-2 on the basis of the clinically approved drugs [16][17][18][19][20][21], and also on the basis of the compounds from different databases or libraries [22][23][24].…”

Boosting the arsenal against COVID-19 through computational drug repurposing

“…The number of studies on in silico drug repurposing against COVID-19 is growing rapidly -among others, worth citing is an interesting approach generating a systems-pharmacology-based network medicine platform that identified the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network and that has identified potential drug repurposing treatments against such interactions [6]. Moreover, a virtual screening approach was used to investigate the FDA-approved LOPAC library and to predict drugs able to minimize the interaction between the viral spike (S)-protein and ACE2 host cell receptor [7]; in an additional report, a novel deep learning platform was used to identify top potential inhibitors of the SARS-CoV-2 main protease by screening 1.3 billion compounds [8]. These types of reports probably represent just a tip of the iceberg of ongoing drug repurposing investigations, the results of which will appear in the coming weeks.…”