High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

Abstract

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the SARS-CoV-2 virus causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top- ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.

In Silico Identification of Potential Natural Product Inhibitors of Human Proteases Key to SARS-CoV-2 Infection

“…To expedite this search for anti-COVID drugs, several computational studies have used homology modeling or published crystal structures of SARS-CoV-2 proteins, molecular docking and diverse small molecule libraries, to predict potential inhibitors of SARS-CoV-2 proteins including among existing approved drugs for repurposing and natural compounds (see e.g., [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]). In comparison, fewer computational studies [ 16 , 19 ] have focussed on identification of potential inhibitors of host factors.…”

Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease

“…Determination of the high-resolution X-ray structures of SARS-CoV-2 main protease (M Pro ) in ligand-bound and unbound states (Berman et al., 2000 ; http://www.rcsb.org/pdb/ ) laid the foundation not only for understanding the function and molecular mechanism of the enzyme action, but also for developing novel effective SARS-CoV-2 inhibitors by direct methods of computer-aided drug design (e.g. Bhardwaj et al., 2020 ; Fischer et al., 2020 ; Gupta et al., 2020 ; Islam et al., 2020 ; Jin et al., 2020 ; Joshi et al., 2020 ; Khan et al., 2020 ; Olubiyi et al., 2020 ; Pant et al., 2020 ; Sarma et al., 2020 ; Ton et al., 2020 ; Vega-Valdez et al., 2020 ; Wahedi et al., 2020 ; Zhang et al, 2020 ). In particular, SARS-CoV-2 M Pro structure in the complex with the high affinity ligand X77 that is potent non-covalent inhibitor of SARS-COV-2 M Pro was recently deposited in the Protein Data Bank (PDB ID: 6W63, http://www.rcsb.org/pdb/ ).…”

Network analytics for drug repurposing in COVID-19

“…Some of these drugs could have an inhibitory effect on the main protease (e.g. dabigatran etexilate [ 56 , 57 ], dasatinib [ 58 ], ellagic acid [ 59 , 60 ], radotinib [ 61 ]), on the papain-like protease (caffeine [ 62 ], phenformin [ 63 ], ximelagatran [ 64 ]) or on the RNA-dependent RNA polymerase (e.g. docetaxel [ 63 ], eribulin [ 65 ], nilotinib [ 66 ], pelitinib [ 67 ]), as well as on the interaction between the spike and ACE2 (e.g.…”