Computational Screening of Inhibitory Compounds for SARS-Cov-2 3CL Protease with a Database Consisting of Approved and Investigational Chemicals

Abstract

Computational screening is one of the fundamental techniques in drug discovery. Each compound in a chemical database is bound to the target protein in virtual, and candidate compounds are selected from the binding scores. In this work, we carried out combinational computation of docking simulation to generate binding poses and molecular mechanics calculation to estimate binding scores. The coronavirus infectious disease has spread worldwide, and effective chemotherapy is strongly required. The viral 3-chymotrypsinlike (3CL) protease is a good target of low molecular-weight inhibitors. Hence, computational screening was performed to search for inhibitory compounds acting on the 3CL protease. As a preliminary assessment of the performance of this approach, we used 51 compounds for which inhibitory activity had already been confirmed. Docking simulations and molecular mechanics calculations were performed to evaluate binding scores. The preliminary evaluation suggested that our approach successfully selected the inhibitory compounds identified by the experiments. The same approach was applied to 8820 compounds in a database consisting of approved and investigational chemicals. Hence, docking simulations, molecular mechanics calculations, and re-evaluation of binding scores including solvation effects were performed, and the top 200 poses were selected as candidates for experimental assays. Consequently, 25 compounds were chosen for in vitro measurement of the enzymatic inhibitory activity. From the enzymatic assay, 5 compounds were identified to have inhibitory activities against the 3CL protease. The present work demonstrated the feasibility of a combination of docking simulation and molecular mechanics calculation for practical use in computational virtual screening.

Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis

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Sticklac-Derived Natural Compounds Inhibiting RNase H Activity of HIV-1 Reverse Transcriptase

“…The narrowing down of the compounds for the assay was cost-effective and time-saving for experiments. The in silico screening was similar to that performed in a previous work . Briefly, docking simulations were carried out for the individual compounds to generate binding poses to the target domain.…”

“…Computational analysis is indispensable for screening hit chemicals and for rational drug design . In this work, we applied in silico screening to a collection of 400 natural compounds to select candidates for an experimental assay.…”

Exploratory Studies on Amide Bond Replacement of a SARS-CoV-2 Main Protease Inhibitor Utilizing a Chloroalkene Dipeptide Isostere

“…At present, there are two authorized inhibitors against SARS-CoV-2 M pro : nirmatrelvir (Paxlovid TM , which is a combination of nirmatrelvir and ritonavir tablets, Pfizer Inc.) (Owen et al 2021) and ensitrelvir fumaric acid (Xocova ® , Shionogi & Co., Ltd.) (Unoh et al 2022). In addition, many other M pro inhibitors have been developed to date (Hoffman et al 2020;Qiao et al 2021;Bai et al 2022;Xia et al 2021;Ma et al 2021;Wang et al 2022;Ma et al 2022;Tsuji et al 2023;Maehara et al 2022;Hasegawa et al 2022;Miwa et al 2023;Tan et al 2023;Huang et al 2023). However, there are some reports on emergence of nirmatrelvir-resistant SARS-CoV-2 variants (Iketani et al 2023;Ullrich et al 2022;Hu et al 2023;Yang et al 2022) and existence of limitations in combinational dosage of Paxlovid TM with several drugs due to its ritonavir-boosting, which causes inhibition of CYP3A4 that might result in unexpected blood concentration increases of the other drugs (National Institutes of Health 2023).…”