We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50exp). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50exp. Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50exp (pIC50exp = −0.1552·ΔΔGcom + 5.0448, R2 = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50pre reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles.

We have designed new potent inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt) using structure-based molecular design.

Plasmepsin II (PlmII), an aspartic protease expressed in the food vacuole of Plasmodium falciparum (pf), cleaves the hemoglobin of the host during the erythrocytic stage of the parasite life cycle. Various peptidomimetic inhibitors of PlmII reported so far discriminate poorly between the drug target and aspartic proteases of the host organism, e.g., human cathepsin D (hCatD). hCatD is a protein digestion enzyme and signaling molecule involved in a variety of physiological processes; therefore, inhibition of hCatD by PlmII inhibitors may lead to pathophysiological conditions. In this study, binding of PlmII inhibitors has been modeled using the crystal structures of pfPlmII and hCatD complexes to gain insight into structural requirements underlying the target selectivity. A series of 26 inhibitors were modeled in the binding clefts of the pfPlmII and hCatD to establish QSAR models of the protease inhibition. In addition, 3D-QSAR pharmacophore models were generated for each enzyme. It was concluded that the contributions of the P 2 and P 3¢ residues to the inhibitor's binding affinity are responsible for the target selectivity. Based on these findings, new inhibitor candidates were designed with predicted inhibition constants K