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Integrated computational approaches for  Mycobacterium tuberculosis  ( Mtb ) are useful to identify new molecules that could lead to future tuberculosis (TB) drugs. Our approach uses information derived from the TBCyc pathway and genome database, the Collaborative Drug Discovery TB database combined with 3D pharmacophores and dual event Bayesian models of whole-cell activity and lack of cytotoxicity. We have prioritized a large number of molecules that may act as mimics of substrates and metabolites in the TB metabolome. We computationally searched over 200,000 commercial molecules using 66 pharmacophores based on substrates and metabolites from  Mtb  and further filtering with Bayesian models. We ultimately tested 110 compounds  in vitro  that resulted in two compounds of interest, BAS 04912643 and BAS 00623753 (MIC of 2.5 and 5 μg/mL, respectively). These molecules were used as a starting point for hit-to-lead optimization. The most promising class proved to be the quinoxaline di -N -oxides, evidenced by transcriptional profiling to induce mRNA level perturbations most closely resembling known protonophores. One of these, SRI58 exhibited an MIC = 1.25 μg/mL versus  Mtb  and a CC 50  in Vero cells of >40 μg/mL, while featuring fair Caco-2 A-B permeability (2.3 x 10 −6  cm/s), kinetic solubility (125 μM at pH 7.4 in PBS) and mouse metabolic stability (63.6% remaining after 1 h incubation with mouse liver microsomes). Despite demonstration of how a combined bioinformatics/cheminformatics approach afforded a small molecule with promising  in vitro  profiles, we found that SRI58 did not exhibit quantifiable blood levels in mice.

Combining Metabolite-Based Pharmacophores with Bayesian Machine Learning Models for Mycobacterium tuberculosis Drug Discovery