Molecular Modeling of Enoyl Acyl Carrier Protein Reductase Inhibitors for Mycobacterium tuberculosis and their Pharmacokinetic Predictions
Narcisse Fidèle Zonon
Laboratory of Fundamental and Applied Physics, University of Nangui Abrogoua, Abidjan, Côte d’Ivoire.
Logbo Mathias Mousse *
Laboratory of Fundamental and Applied Physics, University of Nangui Abrogoua, Abidjan, Côte d’Ivoire.
Koffi N’Guessan Placide Gabin Allangba
Laboratory of Fundamental and Applied Physics, University of Nangui Abrogoua, Abidjan, Côte d’Ivoire and Physics Pedagogical Unit, Laboratory of Environmental Science and Technology, University Jean Lorougnon Guédé, Daloa, Côte d’Ivoire and Department of Medical Physics, University of Trieste and International Centre for Theoretical Physics (ICTP), Trieste, Italy.
Koffi Charles Kouman
Laboratory of Fundamental and Applied Physics, University of Nangui Abrogoua, Abidjan, Côte d’Ivoire.
Eugene Megnassan
Laboratory of Fundamental and Applied Physics, University of Nangui Abrogoua, Abidjan, Côte d’Ivoire and Laboratory of Structural and Theoretical Organic Chemistry, University Felix Houphouët Boigny, Abidjan, Côte d’Ivoire and ICTP-UNESCO, QLS, Strada Costiera 11, I 34151 Trieste, Italy.
*Author to whom correspondence should be addressed.
Abstract
Tuberculosis (TB) is a deep public health concern worldwide worsened by reported multi drugresistant (MDR) and extensively drug- resistant (XDR) stralins of Mycobacterium tuberculosis, the causative agent of the disease. A new class of thiadiazole inhibitors were reported to inhibit the enoyl-acyl transporter protein reductase (InhA) of Mycobacterium tuberculosis (MTb). We performed here the computer-aided molecular design of novel thiadiazole (TDZ) inhibitors of InhA by in situ modifying the reference crystal structure of (S)-1-(5-((1-(2,6-difluorobenzyl)-1 H-pyrazol-3yl)amino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)ethanol-InhA (PDB code: 4BQP). Thus a training set of 15 hybrids with known inhibition potency \(\left(\mathrm{IC}_{50}^{\exp }\right)\) was selected to establish a onedescriptor quantitative structure-activity relationship (QSAR) model resulting in a linear correlation between the Gibbs free energy (GFE) during the formation of the InhA-TDZ complex and \(\mathrm{IC}_{50}^{\mathrm{exp}}\left(\mathrm{plC} \mathrm{C}_{50} \exp ==-0.29 \mathrm{x} \Delta \Delta \mathrm{G}_{\mathrm{com}}+8.13 ; \mathrm{n}=15 ; \mathrm{R}^2=0.92, \mathrm{R}^2{ }_{\mathrm{xv}}=0.91 ;\right.\) F-test of \(142.6 ; \sigma=0.21 ; \alpha>\) \(\left.95 \% ; R^2-R_{x v}^2=0.01\right)\). The 3D pharmacophore model \((\mathrm{PH} 4)\) generated from the active conformations of TDZs ( \(\mathrm{pIC}_{50}^{\mathrm{exp}}=0.93 \times \mathrm{pIC}_{50}^{\text {pred }}+0.47 ; \mathrm{n}=15 ; \mathrm{R}^2=0.97 ; \mathrm{R}_{\mathrm{xv}}=0.94 ;\) F-test of \(215.45 ; \sigma=0.17 ; \alpha>98 \% ; R^2-R_{x v}^2=0.03\) ) served as a virtual screening tool for new analogs from a virtual library (VL). The combination of molecular modeling and \(\mathrm{PH} 4\) in silico screening of (\(\mathrm{VL}\)) resulted in the identification of novel potent antitubercular agent candidates with favorable pharmacokinetic profiles of which the six best hits predicted inhibitory potencies \(\mathrm{IC}_{50}^{\text {pre }}\) in the sub nanomolar range \((0.1-0.2 \mathrm{nM})\).
Keywords: Tuberculosis, enoyl-acyl carrier protein reductase (InhA), molecular modeling, QSAR models, pharmacophore, combinatorial library, ADME properties prediction