Rational design of FAK inhibitors for autoimmune therapy: a SAR and molecular modeling approach for chemically driven drug discovery

Abstract

Focal adhesion kinase (FAK) is a critical regulator of cellular processes such as migration, adhesion, survival, and differentiation, making it a promising therapeutic target for autoimmune diseases, cancer immunotherapy, chronic inflammation, T-cell modulation, and fibrosis-related tissue remodeling. This study evaluates the FAK inhibitory potential of a series of molecules as potential therapeutics for autoimmune diseases. A dataset of 437 compounds was used to develop a quantitative structure–activity relationships (QSAR) model via Monte Carlo optimization, utilizing SMILES-based descriptors and four target functions (TF1–TF4). The TF2 model demonstrated excellent predictive performance (R² = 0.805, Q² = 0.798, R_rand² = 0.020, R_test² = 0.620), identifying key structural features responsible for activity and guiding the design of nine potent inhibitors. The prediction of pharmacokinetic analysis (ADMET) indicated favorable drug-like properties, with no blood–brain barrier penetration. Molecular docking studies revealed strong interactions between the inhibitors and the FAK active site, with significant hydrogen bonding and hydrophobic interactions, particularly in compounds L6, L8, and L9. Molecular dynamics simulations confirmed the stability of these interactions, high binding affinity, and favorable binding free energy. These findings support the therapeutic potential of the newly designed inhibitors and position FAK as a viable target for autoimmune disease modulation, immunotherapy, and treatments for inflammation-related disorders.