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 ie R 2= 0.9181, Standard deviation ie SD= 0.3305, variance ratio ie F= 85.9) and eleven test sets (cross-validation correlation coefficient ie Q 2= 0.6745, Root Mean Square Error ie RMSE= 0.65, Pearson R= 0.8427, P= 1.21 E-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.