Computational Studies on Imidazo[1,2-a] Pyridine-3-Carboxamide Analogues as Antimycobacterial Agents: Common Pharmacophore Generation, Atom-based 3D-QSAR, Molecular dynamics Simulation, QikProp, Molecular Docking and Prime MMGBSA Approaches

Suraj N Mali,Hemchandra K Chaudhari

doi:10.2174/1874844901805010012

Abstract

Background: IMB-1402, Q203 and ND09759 analogs were found to have strong efficiency against Multi-drug-resistant tuberculosis (MDR-TB)/Extensively drug-resistant tuberculosis (XDR-TB) strains. Objectives: To know the structural necessities for imidazo[1,2-a]pyridine-3-carboxamide analogues, we intended to develop the ligand-based pharmacophore, Quantitative structure–activity relationship models(3D-QSAR model). We also performed Molecular docking, molecular simulation and Prime/Molecular Mechanics Generalized Born Surface Area (Prime/MM-GBSA) studies. Methods: All the studies like Common pharmacophore hypothesis generation, Atom based 3D-QSAR study, Prime MMGBSA, Docking, Qikprop, and Molecular dynamics simulation were processed using various modules incorporated within the maestro software interface from Schrodinger, LLC, New York USA (release 2017). Results: The common pharmacophore hypothesis(CPH) generation resulted in a five-featured hypothesis HHPRR, containing 1 positive, 2 hydrophobic and 2 aromatic rings. An Atom-based 3D-QSAR model was predicted for twenty seven training sets (a correlation coefficient i.e.R2= 0.9181,Standard deviation i.e.SD =0.3305, variance ratio i.e. F = 85.9) and eleven test sets (cross-validation correlation coefficient i.e.Q2 =0.6745, Root Mean Square Error i.e. RMSE = 0.65, Pearson R = 0.8427, P=1.21E-12) compounds employing alignment based on CPH. The dataset of thirty-eight molecules was allowed for docking into the active site of pantothenate synthetase (PDBID-3IVX) that shows H-bonding (Hydrogen bonding) interactions with residues Gly158, Met195, Pro38 and additionally shows further Pi-cation interactions with a residue like Hie47. We also obtained good simulation results for1.2ns study. Conclusion: From the results, the generated 3D-QSAR model may be applicable for additional designing of various novel potent derivatives in the future.

Highlights

Tuberculosis (TB) is a global health concern that is caused primarily by Mycobacterium (MTB)
An Atom-based 3D-QSAR model was predicted for twenty seven training sets and eleven test sets compounds employing alignment based on CPH
The dataset 38 molecules were allowed for docking protocol to dock into the active site of pantothenate synthetase (PDBID-3IVX), which indicates hydrogen bond interactions with residues Gly158, Met195, Pro38 and shows further Pi-cation interactions with a residue like Hie47

Summary

Introduction

Tuberculosis (TB) is a global health concern that is caused primarily by Mycobacterium (MTB). The emergence of MDR and XDR TB strains has amplified the incidences of TB. In 2012, an estimated 8.6 million individuals suffering from M. tuberculosis and 1.3 million died from the disease, together with 320,000 deaths among HIV-positive individuals [2, 3]. Two candidates Q203 and ND09759 were reported to possess inhibitory potency against each MDR and XDR strains Fig. We intended to develop the pharmacophore model that primarily signifies the importance of specific structural features. The important features include hydrophobicity, nature of atoms, the functional groups and aromatic features of molecules required for targeting a selected protein. A 3D-QSAR model (Atom-based) was conjointly developed for relating the SAR between a dataset of molecules using PHASE (Schrödinger, 2017) with their activities [4]. IMB-1402, Q203 and ND09759 analogs were found to have strong efficiency against Multi-drug-resistant tuberculosis (MDRTB)/Extensively drug-resistant tuberculosis (XDR-TB) strains

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Conclusion