Focal adhesion kinase (FAK) plays a primary role in regulating the activity of many signaling molecules. Increased FAK expression has been associated in a series of cellular processes like cell migration and survival. FAK inhibition by an anti cancer agent is critical. Therefore, it is of interest to identify, modify, design, improve and develop molecules to inhibit FAK. Solanesol is known to have inhibitory activity towards FAK. However, the molecular principles of its binding with FAK is unknown. Solanesol is a highly flexible ligand (25 rotatable bonds). Hence, ligand-protein docking was completed using AutoDock with a modified contact based scoring function. The FAK-solanesol complex model was further energy minimized and simulated in GROMOS96 (53a6) force field followed by post simulation analysis such as Root mean square deviation (RMSD), root mean square fluctuations (RMSF) and solvent accessible surface area (SASA) calculations to explain solanesol-FAK binding.

Kinase by in silico strategies32 Focal adhesion kinase (FAK) plays a primary role in regulating the activity of many 33 signaling molecules. Increased FAK expression has been implicated in a series of cellular 34 processes, including cell migration and survival. Inhibiting the activity of FAK for cancer 35 therapy is currently under investigation. Hence, FAK and its inhibitors has been the subject 36 of intensive research. To understand the structural factors affecting inhibitory potency, 37 kinetic analysis, molecular docking and molecular dynamics simulation were studied in 38 this project. Though, Solanesol was found have inhibitory activities towards FAK, no in 39 silico tests were ever done on the same. 40 Due to high flexibility of Solanesol (Rotatable bonds = 25), it is difficult to analyze using 41 normal docking protocols. This paper introduces a novel method to dock and analyze 42 molecules with high flexibility based on weighed contact based scoring method. This 43 method uses blind docking technique, which was developed for protein peptide docking 44 method, to generate conformations which were used to calculate contact based weights of 45 residues. This method reveals the possible binding site for the small molecule. An 46 exhaustive docking search on the acquired area reveals the docked confirmation of the 47 compound. The final docked conformation was subjected to molecular dynamics to 48 understand of binding stability. This study is in a good agreement with experimental results 49 which shows Solanesol binds at ATP binding site and inhibit the phosphorylation of Focal 50 Adhesion Kinase.51