Discovery of pyrimidoindol and benzylpyrrolyl inhibitors targeting SARS-CoV-2 main protease (M pro ) through pharmacophore modelling, covalent docking, and biological evaluation.

Autor: Mahgoub RE; College of Pharmacy, Al Ain University, Abu Dhabi, 112612, United Arab Emirates; AAU Health and Biomedical Research Centre, Al Ain University, Abu Dhabi, 112612, United Arab Emirates., Mohamed FE; Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, 15551, United Arab Emirates., Ali BR; Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, 15551, United Arab Emirates; Zayed Centre for Health Sciences, United Arab Emirates University, Al-Ain, 15551, United Arab Emirates., Ferreira J; Science Division, New York University Abu Dhabi, Abu Dhabi, 129188, United Arab Emirates., Rabeh WM; Science Division, New York University Abu Dhabi, Abu Dhabi, 129188, United Arab Emirates., Atatreh N; College of Pharmacy, Al Ain University, Abu Dhabi, 112612, United Arab Emirates; AAU Health and Biomedical Research Centre, Al Ain University, Abu Dhabi, 112612, United Arab Emirates., Ghattas MA; College of Pharmacy, Al Ain University, Abu Dhabi, 112612, United Arab Emirates; AAU Health and Biomedical Research Centre, Al Ain University, Abu Dhabi, 112612, United Arab Emirates. Electronic address: mohammad.ghattas@aau.ac.ae.
Jazyk: angličtina
Zdroj: Journal of molecular graphics & modelling [J Mol Graph Model] 2024 Mar; Vol. 127, pp. 108672. Date of Electronic Publication: 2023 Nov 15.
DOI: 10.1016/j.jmgm.2023.108672
Abstrakt: The main protease (M pro ) enzyme has an imperative function in disease progression and the life cycle of the SARS-CoV-2 virus. Although the orally active drug nirmatrelvir (co-administered with ritonavir as paxlovid) has been approved for emergency use as the frontline antiviral agent, there are a number of limitations that necessitate the discovery of new drug scaffolds, such as poor pharmacokinetics and susceptibility to proteolytic degradation due to its peptidomimetic nature. This study utilized a novel virtual screening workflow that combines pharmacophore modelling, multiple-receptor covalent docking, and biological evaluation in order to find new M pro inhibitors. After filtering and analysing ∼66,000 ligands from three different electrophilic libraries, 29 compounds were shortlisted for experimental testing, and two of them exhibited ≥20% inhibition at 100 μM. Our top candidate, GF04, is a benzylpyrrolyl compound that exhibited the highest inhibition activity of 38.3%, with a relatively small size (<350 Da) and leadlike character. Interestingly, our approach also identified another hit, DR07, a pyrimidoindol with a non-peptide character, and a molecular weight of 438.9 Da, reporting an inhibition of 26.3%. The established approach detailed in this study, in conjunction with the discovered inhibitors, has the capacity to yield novel perspectives for devising covalent inhibitors targeting the COVID-19 M pro enzyme and other comparable targets.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Mohammad A. Ghattas reports financial support was provided by Al Jalila Foundation.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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