Recent Advances of DprE1 Inhibitors against Mycobacterium tuberculosis: Computational Analysis of Physicochemical and ADMET Properties

Abstract

Decaprenylphosphoryl-β-d-ribose 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 ∼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.

DprE1 Inhibitors: Enduring Aspirations for Future Antituberculosis Drug Discovery

“…Amado et al [13b] . performed a comprehensive analysis of physicochemical descriptors and ADMET properties for 1,519 DprE1 inhibitors reported in the literature between 2009 and April 2022.…”

Mycobacterium tuberculosis: Pathogenesis and therapeutic targets

“…In contrast, OPC‐167832 is a carbostyril derivative and TBA‐7371 is a 1,4‐azaindole, both of which are noncovalent DprE1 inhibitors. Recent research have identified a variety of new DprE1 inhibitors, including benzothiazinones containing 2‐benzyl‐2,7‐diazaspiro[3.5]nonane, 116 benzothiopyranones, 117 morpholino‐pyrimidines, 118 hydantoins, 119 thiophene‐arylamides, 120 4‐aminoquinolone piperidine amides, 121 2‐carboxyquinoxalines, 122 N ‐alkyl‐5‐hydroxypyrimidinone carboxamides, 123 selamectin, 124 with promising antimycobacterial activity 125 …”

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

“…Thus far, more than 600 examples of 8-nitro-BTZs have been reported, of which nearly 90% exhibit in vitro activity against M. tuberculosis (MIC < 10 μM). 107 Despite these extensive studies, the effect of side chain at C-2 on the in vitro activity against mycobacteria still lacks a comprehensive understanding. Remarkably, one of two BTZs that have progressed to clinical studies, viz.…”

“…125 An up-to-date in-depth computational analysis and evaluation of physicochemical descriptors and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of a total of 41.500 published DprE1 inhibitors against M. tuberculosis including BTZs can be found in the literature. 107…”