Discovery of Chalcone-Based Hybrid Structures As High Affinity and Site-Specific Inhibitors Against SARS-CoV-2: A Comprehensive Structural Analysis Based on Various Host-Based and Viral Targets

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 May 27

PMID 37240149

Authors

Mehdi Valipour

Silvia Di Giacomo

Antonella Di Sotto

Hamid Irannejad

Affiliations

Soon will be listed here.

Abstract

Previous studies indicated that natural-based chalcones have significant inhibitory effects on the coronavirus enzymes 3CLpro and PLpro as well as modulation of some host-based antiviral targets (HBATs). In this study, a comprehensive computational and structural study was performed to investigate the affinity of our compound library consisting of 757 chalcone-based structures (CHA-1 to CHA-757) for inhibiting the 3CLpro and PLpro enzymes and against twelve selected host-based targets. Our results indicated that CHA-12 (VUF 4819) is the most potent and multi-target inhibitor in our chemical library over all viral and host-based targets. Correspondingly, CHA-384 and its congeners containing ureide moieties were found to be potent and selective 3CLpro inhibitors, and benzotriazole moiety in CHA-37 was found to be a main fragment for inhibiting the 3CLpro and PLpro. Surprisingly, our results indicate that the ureide and sulfonamide moieties are integral fragments for the optimum 3CLpro inhibition while occupying the S1 and S3 subsites, which is fully consistent with recent reports on the site-specific 3CLpro inhibitors. Finding the multi-target inhibitor CHA-12, previously reported as an LTD4 antagonist for the treatment of inflammatory pulmonary diseases, prompted us to suggest it as a concomitant agent for relieving respiratory symptoms and suppressing COVID-19 infection.

Citing Articles

Benzoindolizidine Alkaloids Tylophorine and Lycorine and Their Analogues with Antiviral, Anti-Inflammatory, and Anticancer Properties: Promises and Challenges.

Di Sotto A, Valipour M, Azari A, Di Giacomo S, Irannejad H Biomedicines. 2023; 11(10).

PMID: 37892993 PMC: 10603990. DOI: 10.3390/biomedicines11102619.

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