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ISSN (Print): 2211-3525
ISSN (Online): 2211-3533

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Research Article

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

Author(s): Surabhi Jain*, Smriti Sharma and Dhrubo Jyoti Sen

Volume 20, Issue 5, 2022

Published on: 31 August, 2022

Article ID: e140422203557 Pages: 20

DOI: 10.2174/2211352520666220414094155

Price: $65

Abstract

Background: Field-based 3D-QSAR, homology modelling, molecular docking, and ADMET 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: The objective of this study is to design new anti-tubercular agents using field-based 3D-QSAR and molecular docking approaches and to ascertain the binding manner and drug-likeliness profile of imidazo[1,2-a]pyridine derivatives as antitubercular agents on ATP synthase protein.

Methods: A statistically significant 3D-QSAR model was generated with the dataset of 30 active agonists on ATP synthase whose pIC50 values ranged 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 from3D-QSAR contour maps was used in designing new molecules.

Results: The constructed 3D-QSAR model had a high correlation coefficient (R2=0.9688) and crossvalidation coefficient (Q2=0.9045), and F value (176) at the 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 physicochemical properties, which showed the acidic and hydrophobic nature of the protein. The docking score of dataset compound no. PF19 (-9.97 Kcal/mol) was found to be almost similar to that of bedaquiline (- 10.08 Kcal/mol). Based on previous results from 3D-QSAR modelling and molecular docking, four new molecules were 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 assessability. The findings suggested that these compounds had a strong possibility of becoming ATP-synthase inhibitors.

Conclusion: The various in silico 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.

Keywords: Tuberculosis, bedaquiline, ATP synthase, homology modelling, docking, imidazo[1, 2-a]pyridine, field-based 3D QSAR modelling.

Graphical Abstract

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