Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein

Abstract

The severity of the COVID-19 pandemic has necessitated the search for drugs against SARS-CoV-2. In this study, we explored via in silico approaches myxobacterial secondary metabolites against various receptor-binding regions of SARS-CoV-2 spike which are responsible in recognition and attachment to host cell receptors mechanisms, namely ACE2, GRP78, and NRP1. In general, cyclic depsipeptide chondramides conferred high affinities toward the spike RBD, showing strong binding to the known viral hot spots Arg403, Gln493 and Gln498 and better selectivity compared to most host cell receptors studied. Among them, chondramide C3 (1) exhibited a binding energy which remained relatively constant when docked against most of the spike variants. Chondramide C (2) on the other hand exhibited strong affinity against spike variants identified in the United Kingdom (N501Y), South Africa (N501Y, E484K, K417N) and Brazil (N501Y, E484K, K417T). Chondramide C6 (9) showed highest BE towards GRP78 RBD. Molecular dynamics simulations were also performed for chondramides 1 and 2 against SARS-CoV-2 spike RBD of the Wuhan wild-type and the South African variant, respectively, where resulting complexes demonstrated dynamic stability within a 120-ns simulation time. Protein-protein binding experiments using HADDOCK illustrated weaker binding affinity for complexed chondramide ligands in the RBD against the studied host cell receptors. The chondramide derivatives in general possessed favorable pharmacokinetic properties, highlighting their potential as prototypic anti-COVID-19 drugs limiting viral attachment and possibly minimizing viral infection.

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) to GRP78 (PDB ID: 6VXX) and ACE2 receptors (PDB ID: 6M0J), RdRp (PDB ID: 6M71), 3CLPro (PDB ID: 6LU7), and PLPro (PDB ID: 6W9C) (Fernandez et al, 2021;.…”

“…Visualization and analysis of the enzyme-ligand interactions and residues were done through UCSF Chimera and BIOVIA Discovery Studios (version 4.1) (Africa et al, 2022;de Leon et al, 2021;Fernandez et al, 2021).…”

“…The use of computer-aided drug design and discovery (CADDD) has accelerated drug development to streamline efforts and time in the discovery of compounds for in vitro and in vivo experimental studies (Chaudhary & Mishra, 2016). Among the numerous applications of CADDD is the use of molecular docking, which is commonly used in the discovery for treatment against SARS-CoV-2 (de Fernandez et al, 2021). This strategy is a promising method since it plays a major role in efforts for modern drug discovery and development particularly anti-COVID-19 drugs (Brogi et al, 2022).…”

Combinatorial library screening of quinadoline B derivatives against SARS-CoV-2 RNA-dependent RNA polymerase

“…In COVID-19 drug discovery, several possible drug targets, comprised structural and non-structural proteins, have been exploited in searching novel chemical entities as anti-SARS-CoV-2 agents [10][11][12][13]. Among these targets is the RNA-dependent RNA polymerase (RdRp), which is a multi-domain SARS-CoV-2 protein playing a crucial role in the viral life cycle.…”