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Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor

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...

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Autores principales: Alhadrami, Hani A., Sayed, Ahmed M., Al-Khatabi, Heba, Alhakamy, Nabil A., Rateb, Mostafa E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229550/
https://www.ncbi.nlm.nih.gov/pubmed/34198933
http://dx.doi.org/10.3390/ph14060541
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author Alhadrami, Hani A.
Sayed, Ahmed M.
Al-Khatabi, Heba
Alhakamy, Nabil A.
Rateb, Mostafa E.
author_facet Alhadrami, Hani A.
Sayed, Ahmed M.
Al-Khatabi, Heba
Alhakamy, Nabil A.
Rateb, Mostafa E.
author_sort Alhadrami, Hani A.
collection PubMed
description 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 (IC(50) = 5.4 µM and K(i) = 3.22 µM) of one of the viral key enzymes (i.e., M(Pro)). However, it showed high cytotoxicity toward normal human fibroblasts (CC(50) = 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 M(Pro) 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 M(Pro) testing, was 4.5 times more potent (IC(50) = 1.1 µM and K(i) = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC(50) > 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.
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spelling pubmed-82295502021-06-26 Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor Alhadrami, Hani A. Sayed, Ahmed M. Al-Khatabi, Heba Alhakamy, Nabil A. Rateb, Mostafa E. Pharmaceuticals (Basel) Article 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 (IC(50) = 5.4 µM and K(i) = 3.22 µM) of one of the viral key enzymes (i.e., M(Pro)). However, it showed high cytotoxicity toward normal human fibroblasts (CC(50) = 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 M(Pro) 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 M(Pro) testing, was 4.5 times more potent (IC(50) = 1.1 µM and K(i) = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC(50) > 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. MDPI 2021-06-05 /pmc/articles/PMC8229550/ /pubmed/34198933 http://dx.doi.org/10.3390/ph14060541 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alhadrami, Hani A.
Sayed, Ahmed M.
Al-Khatabi, Heba
Alhakamy, Nabil A.
Rateb, Mostafa E.
Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor
title Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor
title_full Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor
title_fullStr Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor
title_full_unstemmed Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor
title_short Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 M(Pro) Inhibitor
title_sort scaffold hopping of α-rubromycin enables direct access to fda-approved cromoglicic acid as a sars-cov-2 m(pro) inhibitor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229550/
https://www.ncbi.nlm.nih.gov/pubmed/34198933
http://dx.doi.org/10.3390/ph14060541
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