Covalent small-molecule inhibitors of SARS-CoV-2 Mpro: Insights into their design, classification, biological activity, and binding interactions.

Autor: Shawky AM; Science and Technology Unit (STU), Umm Al-Qura University, Makkah, 21955, Saudi Arabia., Almalki FA; Department of Pharmaceutical Sciences, Faculty of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia., Alzahrani HA; Applied Medical Science College, Medical Laboratory Technology Department, Northern Border University, Arar, Saudi Arabia., Abdalla AN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia; Department of Pharmacology and Toxicology, Medicinal And Aromatic Plants Research Institute, National Center for Research, Khartoum, 2404, Sudan., Youssif BGM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt. Electronic address: bgyoussif2@gmail.com., Ibrahim NA; Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt., Gamal M; Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt., El-Sherief HAM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia, Egypt., Abdel-Fattah MM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt., Hefny AA; Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt; School of Pharmacy, University of Waterloo, Kitchener, Ontario, N2G 1C5, Canada., Abdelazeem AH; Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt; Pharmacy Department, College of Pharmacy, Nursing and Medical Sciences, Riyadh Elm University, Riyadh, 11681, Saudi Arabia., Gouda AM; Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt. Electronic address: ahmed.gouda@pharm.bsu.edu.eg.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Nov 05; Vol. 277, pp. 116704. Date of Electronic Publication: 2024 Aug 08.
DOI: 10.1016/j.ejmech.2024.116704
Abstrakt: Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2 infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small-molecule covalent inhibitors has been used in the design and discovery of many highly potent and broad-spectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies, were discussed. The review also describes the potential mechanism of the interaction between these inhibitors and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro, with IC 50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARS-CoV-2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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