Identification of Novel Raf-kinase Inhibitors Using in Silico Virtual Screening for Targeted Cancer Therapy In Silico Discovery of Novel RAF Kinase Inhibitors
Iranian Journal of Pharmaceutical Sciences,
Vol. 22 No. 1 (2026),
26 January 2026
,
Page 376-390
https://doi.org/10.22037/ijps.v22i1.48085
Abstract
Cancer has long been a major health problem; the overexpression of a protein kinase in cell signaling pathways is a common cause of it. Targeted therapy has become a more popular focus of research due to its specificity towards particular protein kinases, compared to conventional chemotherapy, which does not differentiate between normal and cancerous cells. B-Raf is one such protein kinase that is commonly mutated in various types of cancer, including melanoma, colorectal cancer, and prostate cancer. The objective of this study is to identify new inhibitors or candidates for anti-protein kinase drugs targeting the Raf-B protein using the dual strategy of screening novel compounds and repurposing drugs. This research focused on using in silico drug design tools, such as Autodock vina, for virtual screening. We docked and studied 13 candidates that had not yet passed the preclinical phase, and repurposed 29 medications that already had a temporary authorization for use for a different target. This allowed us to predict their physicochemical and pharmacokinetic properties, as well as their binding energies with the B-RAF protein kinase (ID: 6M3M). Our results were promising, yielding three candidates with an excellent binding energy above -10.2 kcal/mol, with candidate 8b (-10.7 kcal/mol, 6-(4-{[(phénylamino)(sulfanyl) méthyl]amino}sphényl)-2-phényl-2,3,4,5-tétrahydropyridazin-3-ol) being the most promising. We also found five molecules from the repurposing with a binding energy above -9.4 kcal/mol, with Uprosertib (-10.3 kcal/mol, N-[(2S)-1-Amino-3-(3,4-difluorophenyl)-2-propanyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furamide) having the highest binding energy, it used in trials studying the treatment of Cancer, Melanoma, Solid Tumours, Cervical Cancer, and HER2/Neu Negative, among others. Importantly, none of these candidates were predicted to pass the blood-brain barrier, making them harmless to the central nervous system. A QSAR study is recommended to provide valuable insights into the ligand-protein interactions and potentially optimize the design of these promising molecules with enhanced potency and selectivity. Also, it is important to conduct further in vitro and in vivo studies to verify their efficacy and safety.
- Cancer
- Targeted therapy
- Protein kinase
- Molecular docking
- Autodock vina
- Drug repurposing
How to Cite
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