Recent advances of DprE1 inhibitors against mycobacterium tuberculosis: computational analysis of physicochemical and ADMET properties

Amado, Patrícia; Woodley, Christopher; Lurdes S. Cristiano, M.; O’Neill, Paul M.

http://hdl.handle.net/10400.1/18918

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Authors

Amado, Patrícia

Woodley, Christopher

Lurdes S. Cristiano, M.

O’Neill, Paul M.

Abstract(s)

D e cap renylp ho sp ho ryl-beta-D-rib os e 2 '-epimerase (DprE1) is a critical flavoenzyme in Mycobacterium tuberculosis, catalyzing a vital step in the production of lipoarabinomannan and arabinogalactan, both of which are essential for cell wall biosynthesis. Due to its periplasmic localization, DprE1 is a susceptible target, and several compounds with diverse scaffolds have been discovered that inhibit this enzyme, covalently or noncovalently. We evaluated a total of similar to 1519 DprE1 inhibitors disclosed in the literature from 2009 to April 2022 by performing an in-depth analysis of physicochemical descriptors and absorption, distribution, metabolism, excretion, and toxicity (ADMET), to gain new insights into these properties in DprE1 inhibitors. Several molecular properties that should facilitate the design and optimization of future DprE1 inhibitors are described, allowing for the development of improved analogues targeting M. tuberculosis.

Keywords

Assay interference compounds Drug discovery Benzothiazione derivatives In-silico Antimycobacterial activity Antitubercular evaluation Noncovalent inhibitors Biological evaluation Compounds pains Small-molecule