Speaker
Koffi Charles Kouman
(Laboratoire de Physique Fondamentale et Appliquée)
Description
We have carried out a computational structure-based design of new potent N-
Benzyl-4-((heteroaryl)methyl)benzamides(BHMB) inhibitors of enoyl-acyl carrier protein
reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of
InhA-BHMBx complexes were prepared by in situ modification of the crystal structure of
InhA-BHMB1 (Protein Data Bank (PDB) entry code: 4QXM), the reference compound of a
training set of 19 BHMBs with known experimental inhibitory potencies (IC50
exp). First, we
built a gas phase quantitative structure-activity relationships (QSAR) model, linearly
correlating the computed enthalpy of the InhA-BHMB complex formation and the IC50
exp
.
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 (∆∆Gcom) of InhA-BHMB complex formation and IC50
exp (pIC50
exp = -0.237∆∆Gcom +
7.8783, R
2 = 0.97), which was further validated with a 3D-QSAR pharmacophore model
generation (PH4).
Primary author
Koffi Charles Kouman
(Laboratoire de Physique Fondamentale et Appliquée)
