QSAR-based design of antitubercular pyrrolidine carboxamides

Tuberculosis affects 10 million people around the world, for this reason, the development of new drugs against M. tuberculosis (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, ∆Gbinding < 0.