Computational Identification of Potential Ligands for SARS-CoV-2 Spike Protein: A Docking Study with Natural Compounds and Antiviral Drugs

Abstract

Alessandro Careglio*

The ongoing global challenge posed by SARS-CoV-2 highlights the urgent need for novel antiviral strategies, particularly targeting the viral Spike protein crucial for host cell entry. This computational study aimed to identify potential ligands for the SARS-CoV-2 Spike protein using molecular docking simulations. Both conventional and covalent docking approaches were employed to screen a diverse set of compounds, including natural products from various plant matrices (cocoa, Hypericum perforatum, Hedera helix, wormwood, sage) and approved or experimental antiviral drugs, with a specific focus on nitrile-containing compounds for covalent interactions with Cysteine 136. For conventional docking, several natural compounds demonstrated high binding affinities. Notably, epicatechin gallate and procyanidin A2 from cocoa, and compounds from Hypericum perforatum (e.g., hypericin, amentoflavone, biapigenin) showed promising scores and favorable ADME profiles. Ivy compounds like hederacoside and alpha-hederin exhibited high scores and were observed to occupy key amino acids within the Spike protein's ACE2 binding interface. Among the antiviral drugs, Ritonavir yielded some of the best docking scores, particularly with the receptor-bound Spike conformation, while Oolonghomobisflavan-A and -B also displayed excellent scores and are known to inhibit COVID proteases.

In covalent docking targeting Cysteine 136, Bauhinin and Bursatellin emerged as top-scoring natural compounds. Among drugs, the beta-blocker Epanolol and the antidepressant Vilazodone showed significant binding to this exposed cysteine residue. This finding for Vilazodone is particularly notable given existing clinical studies suggesting an association between antidepressant use, including Vilazodone, and reduced risk of severe COVID-19 outcomes. In conclusion, this study identifies several promising natural compounds and existing drugs as potential Spike protein ligands through both conventional and covalent binding mechanisms. These findings warrant further experimental validation, potentially exploring the synergistic effects of natural compound mixtures, and investigating the clinical implications of identified drug-protein interactions.

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