Potential Novel Thioether-Amide or Guanidine-Linker Class of SARS-CoV-2 Virus RNA-Dependent RNA Polymerase Inhibitors Identified by High-Throughput Virtual Screening Coupled to Free-Energy Calculations

Abstract

SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new pathogen from the family of Coronaviridae that caused a global pandemic of COVID-19 disease. In the absence of effective antiviral drugs, research of novel therapeutic targets such as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) becomes essential. This viral protein is without a human counterpart and thus represents a unique prospective drug target. However, in vitro biological evaluation testing on RdRp remains difficult and is not widely available. Therefore, we prepared a database of commercial small-molecule compounds and performed an in silico high-throughput virtual screening on the active site of the SARS-CoV-2 RdRp using ensemble docking. We identified a novel thioether-amide or guanidine-linker class of potential RdRp inhibitors and calculated favorable binding free energies of representative hits by molecular dynamics simulations coupled with Linear Interaction Energy calculations. This innovative procedure maximized the respective phase-space sampling and yielded non-covalent inhibitors representing small optimizable molecules that are synthetically readily accessible, commercially available as well as suitable for further biological evaluation and mode of action studies.

Virtual Screening and Quantum Chemistry Analysis for SARS-CoV-2 RNA-Dependent RNA Polymerase Using the ChEMBL Database: Reproduction of the Remdesivir-RTP and Favipiravir-RTP Binding Modes Obtained from Cryo-EM Experiments with High Binding Affinity

“…In this study, I performed a stepwise structure-based virtual screening using two different docking simulations to discover potential drugs that target the RdRp complex:dsRNA using the ChEMBL database [ 9 ], which contains drugs and known bioactive compounds. I expected that the potential drug candidates with anti-SARS-CoV-2 activity obtained from the previous screening, which targeted RdRp (nsp12) largely differed from the results of this study since the previous studies were performed without nsp7, nsp8, and dsRNA [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Interestingly, nine nucleoside triphosphate analogs (adenosine triphosphate, entecavir triphosphate, favipiravir-RTP, remdesivir-RTP, penciclovir triphosphate, lamivudine triphosphate, GTP, GS-461203, 2-chlorodeoxyadenosine triphosphate), which could function as prodrugs, were obtained as hit compounds with high binding affinity.…”

“…The advantage of using the ChEMBL database is that it covers all types of drugs from the preclinical stage to approval. I expected that the hit compounds would largely differ from the candidates obtained from the virtual screenings using the focused and targeted libraries [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Concerning drug repositioning, the ChEMBL database is more suitable for searching for effective known drugs or bioactive compounds when an urgent therapy is necessary and effective drugs are not known.…”

Commercial SARS-CoV-2 Targeted, Protease Inhibitor Focused and Protein–Protein Interaction Inhibitor Focused Molecular Libraries for Virtual Screening and Drug Design

“…The pressure on the scientific community to develop a vaccine or drug has never been greater [ 81 ]. Several SARS-CoV-2 proteins have emerged as potential therapeutic targets for drug development, for example, S-protein and the viral proteases 3CL pro and PL pro [ 25 , 82 , 83 , 84 , 85 ]. With the new potential SARS-CoV-2 targets in mind, we decided to evaluate the commercially available SARS-CoV-2-targeted libraries.…”

Therapeutic Targeting of Innate Immune Receptors Against SARS-CoV-2 Infection

“…Targeting RdRp by an antiviral can be effective because stopping this enzyme will inhibit viral replication, and thus the infection cycle will be blocked ( Zhao J. et al, 2021 ; Jukič et al, 2021 ). Moreover, RdRp has no host cell homolog.…”