Discovering potential inhibitors of Raf proto-oncogene serine/threonine kinase 1: a virtual screening approach towards anticancer drug development

Abstract

Raf proto-oncogene serine/threonine kinase 1 (RAF1 or c-Raf) is a serine/threonine protein kinase crucial in regulating cell growth, differentiation, and survival. Any disruption or overexpression of RAF1 can result in neoplastic transformation and other disorders such as cardiomyopathy, Noonan syndrome, leopard syndrome, etc. RAF1 has been identified as a potential therapeutic target in drug development against various complex diseases, including cancer, due to its remarkable role in disease progression. Here, we carried out a multitier virtual screening study involving different in-silico approaches to discover potential inhibitors of RAF1. After applying the Lipinski rule of five, we retrieved all phytocompounds from the IMPPAT database based on their physicochemical properties. We performed a molecular docking-based virtual screening and got top hits with the best binding affinity and ligand efficiency. Then we screened out the selected hits using the PAINS filter, ADMET properties, and other druglike features. Eventually, PASS evaluation identifies two phytocompounds, Moracin C and Tectochrysin, with appreciable anti-cancerous properties. Finally, all-atom molecular dynamics simulation (MDS) followed by interaction analysis was performed on the elucidated compounds in complex with RAF1 for 200 ns to investigate their time-evolution dynamics and interaction mechanism. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) and Dynamical Cross-Correlation Matrix (DCCM) analyses then followed these results from the simulated trajectories. According to the results, the elucidated compounds stabilize the RAF1 structure and lead to fewer conformational alterations. The results of the current study indicated that Moracin C and Tectochrysin could serve as potential inhibitors of RAF1 after required validation.

Communicated by Ramaswamy H. Sarma

KEYWORDS:

• RAF proto-oncogene serine/threonine protein kinase 1
• natural compounds
• virtual screening
• all-atom molecular dynamics simulation
• MM-PBSA
• DCCM

Acknowledgements

Lamya Ahmed Al-Keridis extends her appreciation to Princess Nourah bint Abdulrahman University Researchers Supporting Project Number PNURSP2023R82, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Disclosure statement

There is no conflict of interest to declare.

Additional information

Funding

This work was supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project Number PNURSP2023R282, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.