Abstract

The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, an antibiotic derived from Streptomyces collinus ATCC19743, which was able to suppress the catalytic activity (IC50 = 5.4 µM and Ki = 3.22 µM) of one of the viral key enzymes (i.e., MPro). However, it showed high cytotoxicity toward normal human fibroblasts (CC50 = 16.7 µM). To reduce the cytotoxicity of this microbial metabolite, we utilized a number of in silico tools (ensemble docking, molecular dynamics simulation, binding free energy calculation) to propose a novel scaffold having the main pharmacophoric features to inhibit MPro with better drug-like properties and reduced/minimal toxicity. Nevertheless, reaching this novel scaffold synthetically is a time-consuming process, particularly at this critical time. Instead, this scaffold was used as a template to explore similar molecules among the FDA-approved medications that share its main pharmacophoric features with the aid of pharmacophore-based virtual screening software. As a result, cromoglicic acid (aka cromolyn) was found to be the best hit, which, upon in vitro MPro testing, was 4.5 times more potent (IC50 = 1.1 µM and Ki = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC50 > 100 µM). This report highlights the potential of MNPs in providing unprecedented scaffolds with a wide range of therapeutic efficacy. It also revealed the importance of cheminformatics tools in speeding up the drug discovery process, which is extremely important in such a critical situation.

Highlights

  • IntroductionThe severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) pandemic is still a serious global concern, and hope is hanging on vaccines to provide enough protection [1,2]

  • One of the tested molecules was α-rubromycin librarylibrary againstagainst the viral of. the tested molecules was α-rubromycin which was which was from recovered from Streptomyces collinus fermentation brothmetabolite

  • With the aid of molecular docking and a subsequent dynamic simulation, we proposed the binding mode of α-rubromycin inside the main protease (MPro) active site

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Summary

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) pandemic is still a serious global concern, and hope is hanging on vaccines to provide enough protection [1,2]. Searching for suitable antiviral medications is highly required to assist vaccines in containing this rapidly evolving infectious disease. Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of. The SARS CoV-2 main protease (MPro) is a key hydrolytic enzyme that can activa the viral polyprotein replication complex (1ab) by recognizing and cleaving its speci amino-acid sequences. It is conserved proteins inactivate the coronavir

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