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

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.