Chemometric modeling, inverse docking, and molecular simulations-driven design for multilayered prioritization of...

Leishmaniasis, a major neglected tropical disease (NTD), affects millions of people globally. Current treatments are plagued by infection relapse, high toxicity, and lengthy regimens. A contemporary study investigated the 2-aminobenzimidazole scaffold for leishmanicidal activity but it was found to be associated with poor exposure and lack of efficacy in vivo. This inspired us to develop a QSAR model of leishmanicidal activity leveraging the reported in vivo leishmanicidal activity data toward Leishmania infantum. Interpretable 2D molecular descriptors were employed so that the key leishmanicidal structural features could be utilized to develop the novel molecules. The QSAR model highlighted key structural features associated with leishmanicidal activity, including hydrophobicity, aromatic ring, hydrogen bond acceptor/donor, as well as hetero-atoms (nitrogen, fluorine, etc.) that enhance activity. Various categories of drugs from DrugBank were screened using the developed QSAR model, followed by inverse docking against the putative protein targets for leishmaniasis, to identify the plausible target of the parent leads. QSAR-guided structural modifications were undertaken to generate potential analogs of the top five parent leads. The analogs were checked for their ADMET profiles, and the protein-ligand interactions stability of the top candidates (DB03231-A6 and DB12269-A4) was assessed by 300 ns molecular dynamics simulation. Free energy landscapes (FEL) of the apo and bound target receptor were constructed to further streamline the prioritized analogs. Upon cumulative retrospection, an analog of DB12269 (N-{5-[2-amino-4-fluro-7-(1-hydroxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-4,6-difluoropyrid-3yl}-2-(5-chloropyrazin-2-yl)acetamide) is proposed for further wet lab validation studies for prospective application against leishmaniasis.