Pemodelan Farmakofor dan Penambatan Molekuler Senyawa Potensial Inhibitor Focal Adhesion Kinase (FAK)

Abstract

Background: Breast cancer was the number one cause of death for women in the world. The development of drug designs with FAK inhibitor activity can be a target in inhibiting the metastatic process of cancer cells. Pharmacophore modeling was a solution in the development and discovery of new drugs that are more selective and targeted in cancer treatment. Computational-based in silico methods are used as preliminary information of the bioactivity, physicochemical properties, pharmacological properties, and pharmacophore of a compound. Objective: To determine the pharmacophore modeling compounds that have the potential as FAK inhibitor candidates and to determine the interaction between the hits compounds and FAK proteins. Method: This study was conducted by creating a pharmacophore database, pharmacophore modeling, validation of modeling methods, virtual screening of pharmacophore features, testing physicochemical properties, validation of molecular docking methods, and molecular docking between compound hits and FAK proteins. Results: This study used the FAK protein (PDB: 6YQ1) with a resolution of 1.78 Å derived from the Homo sapiens organism. In creating the pharmacophore database, 25 active compounds and 1000 decoys compounds were used so that the pharmacophore hits score in model 1 was 0.9253. The validation results of the pharmacophore modeling method obtained an AUC value of 0.78. Continued to the virtual screening stage where from 176 compound hits that were screened, only 120 compound hits were obtained that passed Lipinski's rule of five test. In the validation of molecular docking, an RMSD value of 1.097 Å was obtained. The results of molecular docking obtained 8 compound hits with lower binding affinity values than the comparator compound, Defactinib. Conclusion: The compounds ZINC546941086, ZINC000020518433, ZINC000020624547, and ZINC000020517495 were predicted to have potential FAK inhibitor activity with showed interactions in the active pocket of the FAK protein in the form of hydrogen bonds at amino acid residues GLU 500, CYS 502, ASP 564 and TYR 577.