QSAR-based design of antitubercular pyrrolidine carboxamides

Tuberculosis affects 10 million people around the world, for this reason, the development of new drugs against <i>M. tuberculosis (</i>Mtb) is an urgent issue. Enoyl ACP reductase (InhA) is a relevant biological target because it's the role in the synthesis of mycolic acid, the building block of the cell wall. Here, we propose new anti-tuberculosis candidates based on a family of tested InhA pyrrolidine-carboxamides. The strategy starts building QSAR models using, for the first time, a set of topological-descriptors from QTAIM (LDMtrace, Ndeloc, Ntotal, and Max_eigenv), hydrogen bond energy (HB) of Docking simulations, and standard QSAR molecular-descriptors (MATS4m, VE1_Dzp, and RDF70m). The model with the best performance displays robust external and internal validation parameters. Finally, based on the most reliable QSAR model, a set of new molecules were proposed; six of them (p69, p71, p73, p75, p77, and p78) show an efficient calculated IC₅₀ and adequate ADMET properties, suggesting an enhanced biological activity. Molecular Dynamics and MM/PBSA results show that p71 is the most reliable candidate for the inhibition of InhA, displaying a stable complex p71-InhA along 200 ns of simulation and a negative free binding energy, ∆G_binding < 0.