Title:An In silico Study of Imidazo[1,2-a]pyridine Derivatives with Homology
Modelled F1F0 ATP Synthase Against Mycobacterium Tuberculosis
Volume: 20
Issue: 5
Author(s): Surabhi Jain*, Smriti Sharma and Dhrubo Jyoti Sen
Affiliation:
- Faculty of Pharmacy, B. Pharmacy College Rampura-Kakanpur, Gujarat Technological University, Panchmahals, Gujarat,
India
Keywords:
Tuberculosis, bedaquiline, ATP synthase, homology modelling, docking, imidazo[1, 2-a]pyridine, field-based 3D QSAR modelling.
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.
