Discovery of novel ALK2 inhibitors of pyrazolo-pyrimidines: A computational study

Abstract

ALK2 is a serine/threonine kinase, involved in different signaling pathways and associated with cell proliferation and differentiation. The present study includes development of pharmacophore, 3-D QSAR, docking and virtual screening studies on 30 different pyrazolo[1,5-a]pyrimidine derivatives. The pharmacophore study provides ARRR_2 hypothesis with four different features essential for ALK2 kinase inhibitory activity. The 3 D-QSAR study determined the statistically significant model by using partial least-square regression (PLS) method with R² value of 0.9711 and Q² value of 0.6846. Validation of 3 D-QSAR has been performed by LOO cross-validation method where with R²CV value of 0.56. The virtual screening study on ZINC database provides compounds such as ZINC66091638, ZINC43524105, ZINC19458227 and ZINC72441013 involved good binding interactions (docking scores −8.91, −7.40, −8.43, and −9.47, respectively) with ALK2 kinase (PDB ID: 3Q4U). The docking study of pyrazolo-pyrimidines derivatives found potent compounds, 7i, 13r, 13d, and 21 with docking scores −9.83, −9.75, −9.76, and −9.75, respectively. The important interactions with amino acid residues were HID 286, ASN341. ADME properties further assist to provide important structural features of ALK2 kinase. The present study may be help to medicinal scientists in the direction to develop potent inhibitors against ALK2 kinase.

Communicated by Ramaswamy H. Sarma

Keywords:

• 3-D QSAR
• ADME
• 3Q4U
• virtual screening
• ALK2

Acknowledgements

The authors gratefully acknowledge Indian Council of Medical Research (ICMR), New Delhi for providing Research Associate Fellowship (SRF) to Mr. Vivek Asati (SRF No.-45/14/2019-BIO/BMS) in the Department of Pharmaceutical Sciences, Dr HS Gour University, Sagar.

Disclosure statement

No potential conflict of interest was reported by the author(s).