Computational investigation of novel pyrimidine derivatives as potent FAK inhibitors via 3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis

Abstract

Focal adhesion kinase is upregulated in various types of cancer and has become an important research target for the development of more effective anticancer drugs. Herein, a dataset containing 31 pyrimidine-based derivatives as FAK inhibitors was used to develop new and effective FAK inhibitors through molecular modeling, three-dimensional quantitative structure–activity relationship analysis, molecular docking, and molecular dynamics simulation. The best comparative molecular similarity index analysis CoMSIA/HD model (Q² = 0.699, R² = 0.931, R²_test = 0.815) passed all validation parameters, confirming its reliability and predictability. The contour maps showed that the hydrophobic and donor fields have a more significant impact on the bioactivities of the inhibitors. Consequently, four new FAK inhibitors (D1–D4) were developed with higher predicted inhibitory activity. The interaction mode between the new compounds (D1–D4) and the FAK receptor (PDB ID: 6I8Z) was investigated by molecular docking simulation, which showed good binding energy through the creation of hydrogen and hydrophobic bonds with the key residues of the protein, such as Cys502, Ile428, Leu553, Leu567, and Leu501. These new inhibitors had good oral bioavailability and were non-toxic based on their ADMET properties. Furthermore, the most suitable candidate, D3, the most active of the series, 36, and Defactinib as a reference drug were simulated by molecular dynamics for 100 ns, and their binding free energies were determined using the MM–PBSA method. The MD results confirmed the docking results and showed that compound D3 had satisfactory stability with ΔG_binding = −158.362 kJ mol⁻¹ in the active site of the FAK receptor compared with Defactinib with ΔG_binding = −120.872 kJ mol⁻¹. Finally, retrosynthesis tools suggested methods for the synthesis of compound D3 as the most potential therapeutic FAK inhibitor. In conclusion, this study provides theoretical guidelines for the development and synthesis of new FAK inhibitors.