An In silico Study of Imidazo[1,2-a]pyridine Derivatives with Homology Modelled F1F0 ATP Synthase Against Mycobacterium Tuberculosis

Abstract

Aim: To ascertain the binding manner and drug-likeliness profile of imidazo[1,2-a]pyridine derivatives as antitubercular agents on ATP synthase protein. Background: : Field-based 3D-QSAR, Homology modelling, Molecular Docking and ADME-T studies have been carried out to determine the binding mode and drug likeliness profile of imidazo[1,2-a]pyridine derivatives as anti-tubercular agents. Objective: To design new anti-tubercular agents using Field- based 3D-QSAR and molecular docking approach. Methods: A statistically significant 3D-QSAR model was generated with the dataset of 30 active agonists on ATP synthase whose pIC50 values range from 4.0 µM to 8.30 µM. The same dataset was analysed for ADME-T properties and docked to the homology modeled ATP synthase protein. Moreover, information from 3D-QSAR contour maps was used in designing of new molecules. Results: The constructed 3D-QSAR model had a high correlation coefficient (R2=0.9688) and cross-validation coefficient (Q2=0.9045) and F value (176) at 3 component PLS factor. The homology modeled protein ‘ac9’ was validated with various parameters like Ramachandran plot (92.5 %), ERRAT plot (98.43 %), and ProSA (-1.78 chain ‘C’; -2.74 chain ‘A’). The protein was also examined for physico-chemical properties which showed the acidic and hydrophobic nature of protein. The docking score of dataset compound no. PF19 (-9.97 Kcal/mol) was found to be almost similar with that of Bedaquiline (-10.08 Kcal/mol). Based on previous results from 3D-QSAR and Docking, four new molecules was designed. The newly designed molecules (M1-M4) were docked amongst them M3 (-9.82 Kcal/mol) scored the highest. They were further analysed for drug-likeliness, ADME-T and synthetic assesbility. The findings suggested that these compounds had a strong possibility to become ATP-synthase inhibitors. Conclusion: The various Insilico approaches used in the present study offer new avenues for designing novel molecules against ATP synthase from M. tuberculosis and can be employed for the drug discovery programme.