Abstract
Synthetic lethality, involving the simultaneous deactivation of two genes, plays a critical role in disrupting vital cellular functions or prompting cell death. This study delves into the impact of synthetic lethality within cancer research, specifically examining the interplay between the Focal Adhesion Kinase (FAK) and Neurofibromin 2 (NF2) genes. While deactivating FAK or NF2 individually has minimal impact, their combined deactivation highlights the vital significance of their synthetic lethal interaction. Hence, the principal aim of this study is to direct our efforts towards the inhibition of the FAK gene, a venture of notable significance. The NF2 gene is responsible for producing Merlin, a tumor suppressor protein that is often deactivated in schwannoma, meningioma, and malignant mesothelioma. The inhibition of the FAK gene is pivotal, given its pivotal role in the synthetic lethal interplay with NF2/Merlin, promising substantial prospects for the progression of cancer treatment strategies. This investigation has the capacity to propel forward inventive therapeutic methodologies, harnessing the potential of synthetic lethal interactions within cancer cells, and forging a path towards more refined and efficacious interventions in cancer treatment. The ongoing advancements in developing new FAK inhibitors highlight the significance of this strategy in cancer treatment. Despite extensive research efforts, no FAK inhibitor has been approved for clinical use. This emphasizes the urgent need to create new FAK inhibitors with improved anti-tumor properties. The small molecule FAK inhibitor candidates identified in our study show potential for making a groundbreaking contribution in this field. Employing docking and (1ns, 10ns and 100ns) molecular dynamics (MD) simulations, we evaluated FAK inhibitor complex stability, unveiling intricate interactions. Following of molecular dynamics simulations, the MM/GBSA scores for Amprenavir, Bosutinib, Ferric derisomaltose, Flavin adenine dinucleotide, Lactulose and Tafluprost were determined to be -72,81, -71,84, -76.70, -69.09, -74.86, -65.77 kcal/mol, respectively. These molecules have been evaluated as potential candidate drugs based on these scores. This study lays a foundation for novel therapeutics, holding promise for diverse cancer treatments through our computational framework.