Virtual Combinatorial Library Screening of Quinadoline B Derivatives against SARS-CoV-2 RNA-Dependent RNA Polymerase

Abstract

The unprecedented global health threat of SARS-CoV-2 has sparked a continued interest in discovering novel anti-COVID-19 agents. To this end, we present here a computer-based protocol for identifying potential compounds targeting RNA-dependent RNA polymerase (RdRp). Starting from our previous study wherein, using a virtual screening campaign, we identified a fumiquinazolinone alkaloid quinadoline B (Q3), an antiviral fungal metabolite with significant activity against SARS-CoV-2 RdRp, we applied in silico combinatorial methodologies for generating and screening a library of anti-SARS-CoV-2 candidates with strong in silico affinity for RdRp. For this study, the quinadoline pharmacophore was subjected to structural iteration, obtaining a Q3-focused library of over 900,000 unique structures. This chemical library was explored to identify binders of RdRp with greater affinity with respect to the starting compound Q3. Coupling this approach with the evaluation of physchem profile, we found 26 compounds with significant affinities for the RdRp binding site. Moreover, top-ranked compounds were submitted to molecular dynamics to evaluate the stability of the systems during a selected time, and to deeply investigate the binding mode of the most promising derivatives. Among the generated structures, five compounds, obtained by inserting nucleotide-like scaffolds (1, 2, and 5), heterocyclic thiazolyl benzamide moiety (compound 3), and a peptide residue (compound 4), exhibited enhanced binding affinity for SARS-CoV-2 RdRp, deserving further investigation as possible antiviral agents. Remarkably, the presented in silico procedure provides a useful computational procedure for hit-to-lead optimization, having implications in anti-SARS-CoV-2 drug discovery and in general in the drug optimization process.

Attenuation of Lipopolysaccharide-Induced Inflammatory Responses through Inhibition of the NF-κB Pathway and the Increased NRF2 Level by a Flavonol-Enriched n-Butanol Fraction from Uvaria alba

“…Molecular docking methodologies are used for predicting the binding behavior of ligands onto various receptors. ,− In this study, all molecular docking experiments were performed on the University of California San Francisco (UCSF) Chimera platform . The three-dimensional structures of the proteins were retrieved from the RCSB protein data bank () added to the docking platform in PDB format.…”

Flavonoids from Uvaria alba attenuate LPS-induced inflammatory responses by suppressing NF-κB activation in RAW 264.7 macrophages: In silico and in vitro perspectives

“…Molecular docking methodologies are used for predicting the binding behavior of ligands onto various receptors (Brogi et al, 2022;de Leon et al, 2021;Fernandez et al, 2021;Quimque et al, 2021a). In this study, all molecular docking experiments were performed on the UCSF Chimera platform (Pettersen et al, 2004).…”

Virtual Screening of Cyanobacterial Metabolites as Inhibitors of SARS-CoV-2 Host Cell Entry, Viral Replication, and Host Immunity Modulation Infective Mechanisms

“…Two target protein sites important for infectivity (spike RBDs for ACE2 and GRP78) and three non-structural proteins of SARS-CoV-2 (RdRp, 3CL PRO , and PL PRO ) were chosen as molecular targets. The three-dimensional crystal structures of the following target proteins were retrieved from the RCSB protein data bank (RCSB.org): spike's receptor-binding domain (RBD) for ACE2 (PDB ID: 6M0J) and GRP78 (PDB ID: 6VXX), RdRp (PDB ID: 6M71), 3CL PRO (PDB ID: 6LU7), and PL PRO (PDB ID: 6W9C) (Brogi et al 2022;Fernandez et al 2021;Quimque et al 2021a;Lan et al 2020;Walls et al 2020;Gao et al 2020;Jin et al 2020;Osipiuk et al 2020). PDB structures were retrieved based on previous publications, prioritizing high resolution and comparability of results (Africa et al 2022;de Leon et al 2021;Fernandez et al 2021).…”

“…Among the numerous in silico techniques is molecular docking, which is commonly used in the discovery for treatment against SARS-CoV-2 (de Leon et al Fernandez et al 2021;Quimque et al 2021a). With this, virtual screening streamlines secondary metabolites as drug leads with biological activities against SARS-CoV-2 (Brogi et al 2022;Chaudhary and Mishra 2016;Quimque et al 2021a).…”

“…)(Africa et al 2022;Brogi et al 2022;Fernandez et al 2021;Quimque et al 2020). The ligands were rendered as SYBYL mol2 files in an open-source molecular build software, Avogadro (version 1.1.1)(Hanwell et al 2012).…”