DprE1 Inhibitors: Enduring Aspirations for Future Antituberculosis Drug Discovery.

Autor: Yadav S; Department of Pharmacy, Shri Govindram Seksaria Institute of Technology and Science, 23-Park Road, Indore, Madhya Pradesh, India., Soni A; Department of Pharmacy, Shri Govindram Seksaria Institute of Technology and Science, 23-Park Road, Indore, Madhya Pradesh, India., Tanwar O; Department of Pharmacy, Shri Govindram Seksaria Institute of Technology and Science, 23-Park Road, Indore, Madhya Pradesh, India., Bhadane R; Turku Cellular Microbiology Laboratory (TCML), Åbo Akademi University, 20014, Turku, Finland.; Institute of Biomedicine, University of Turku, 20520, Turku, Finland., Besra GS; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Kawathekar N; Department of Pharmacy, Shri Govindram Seksaria Institute of Technology and Science, 23-Park Road, Indore, Madhya Pradesh, India.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2023 Aug 15; Vol. 18 (16), pp. e202300099. Date of Electronic Publication: 2023 Jun 29.
DOI: 10.1002/cmdc.202300099
Abstrakt: DprE1 is a crucial enzyme involved in the cell wall synthesis of Mycobacterium tuberculosis and a promising target for antituberculosis drug development. However, its unique structural characteristics for ligand binding and association with DprE2 make developing new clinical compounds challenging. This review provides an in-depth analysis of the structural requirements for both covalent and non-covalent inhibitors, their 2D and 3D binding patterns, as well as their biological activity data in vitro and in vivo, including pharmacokinetic information. We also introduce a protein quality score (PQS) and an active-site map of the DprE1 enzyme to help medicinal chemists better understand DprE1 inhibition and develop new and effective anti-TB drugs. Furthermore, we examine the resistance mechanisms associated with DprE1 inhibitors to understand future developments due to resistance emergence. This comprehensive review offers insight into the DprE1 active site, including protein-binding maps, PQS, and graphical representations of known inhibitors, making it a valuable resource for medicinal chemists working on future antitubercular compounds.
(© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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