Integrated computational approach for in silico design of new purinyl pyridine derivatives as B-Raf kinase inhibitors

Abstract

B-Raf is one among the most frequently mutating proto-oncogene which is associated with the serine/threonine Raf kinase family involved in the RAS-RAF-MEK-ERK pathway, which is the most deregulated pathway in human cancers. Mutant B-Raf ^V600E got an excellent scope for investigation in cancer as a potential therapeutic target. Formerly B-Raf^V600E is considered the molecular target for numerous antitumor compounds like purinyl pyridine and pyrimidine derivatives. In the current research work using molecular docking approach of Schrodinger Glide 5.6 version, ligand docking, pharmacophore-based virtual screening, binding free energy calculations of a series of 2-amino purinyl pyridine and pyrimidine derivatives were modeled, their docking values were predicted, that were considered to be potent against B-Raf ^V600E. A five-point hypothesis accompanied by a hydrogen bond acceptor(A), two hydrogen bond donors(D), and two aromatic rings (R) was built with a justifiable R² value of 0.91 and a Q² value of 0.64. Then by using Asinex Elite Synergy database, virtual screening was performed, and identified several potential hits. Subsequently, the molecules which had interactions with the target B-Raf kinase were determined by subjecting the obtained hits for SP and XP docking processes. Finally, for the top leads obtained, binding free energies were accomplished. About 16 new purinyl pyridine molecules were also designed. Almost nine molecules manifested crucial ligand interactions and binding free energies. At the outset, this research paved the way for us in spotting new molecules with B-Raf inhibitory activity, which can further be explored to design molecules with enhanced pharmacokinetic profiles.

Keywords:

• B-Raf kinase
• molecular docking
• pharmacophore based virtual screening
• binding free energy
• purinyl pyridine derivatives
• pyrimidine derivatives

Acknowledgements

The authors gratefully acknowledge Schrodinger LLC, New York for providing us the software. The authors express our gratitude to Department of Chemistry, Osmania University for providing facilities to carry out the research work. One of the authors Vaeshnavi Kashetti thank DST for providing Inspire Fellowship (IF180224).

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary information

Ligand interaction studies of newly designed molecules and Screened hits obtained from Asinex Elite Synergy are given in Supplementary information.

Additional information

Funding

This research was made possible through grants from Council of Scientific and Industrial Research [02(0379)/19/EMR-II], DST-PURSE-II (2017-2021) and SERB EEQ/2018/000117.