Pharmacophore generation, atom-based 3D-QSAR, HQSAR and activity cliff analyses of benzothiazine and deazaxanthine derivatives as dual A_2A antagonists/MAO‑B inhibitors

Abstract

Dual inhibition of A_2A and MAO-B is an emerging strategy in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, atom-based three-dimensional quantitative structure–activity relationship (3D-QSAR) and hologram quantitative structure–activity relationship (HQSAR) models were generated with benzothiazine and deazaxanthine derivatives. Based on activity against A_2A and MAO-B, two statistically significant 3D-QSAR models (r² = 0.96, q² = 0.76 and r² = 0.91, q² = 0.63) and HQSAR models (r² = 0.93, q² = 0.68 and r² = 0.97, q² = 0.58) were developed. In an activity cliff analysis, structural outliers were identified by calculating the Mahalanobis distance for a pair of compounds with A_2A and MAO-B inhibitory activities. The generated 3D-QSAR and HQSAR models, activity cliff analysis, molecular docking and dynamic studies for dual target protein inhibitors provide key structural scaffolds that serve as building blocks in designing drug-like molecules for neurodegenerative diseases.

Keywords:

• Dual targeting
• Alzheimer’s disease
• Parkinson’s disease
• atom-based 3D-QSAR
• HQSAR
• activity cliff analysis

Acknowledgements

The authors would like to thank the University Grant Commission (UGC), New Delhi and the Technical Education Quality Improvement Program (TEQIP) Phase-II, University of Calcutta, Kolkata, India for financial assistance of the project.