Theoretical Evaluation of 5, 6-Diaroylisoindoline-1,3-dione as Potential Carcinogenic Kinase PAK1 Inhibitor: DFT Calculation, Molecular Docking Study and ADMET Prediction

Background: The carcinogenic kinase PAK1 (p21-activated kinase 1) is associated with the progression of many disorders, including Alzheimer’s disease, various cancers, type2 diabetes and hypertension. Although few synthetic PAK1 inhibitors and herbal therapeutics, such as propolis and curcumin, are available in the market, a comprehensive remedy of PAK1 related ailments is still not studied in detail. Recently, several phthalimidemetal complexes (viz. Λ-FL172, Λ-FL411, called optically active octahedral ruthenium phthalimide complex) were shown as poor inhibition potency toward PAK1. However, for a full understanding of the inhibition of PAK1 about phthalimide analogues, this study has been designed. Methods: This manuscript presents density functional theory (DFT) based computational approaches of aryl derivatives of phthalimide. The DFT was used to calculate the equilibrium geometries, thermodynamic analysis, dipole moment, polarizability, electrostatic potential map, Mulliken, Hirshfeld, NBO population analysis, frontier molecular orbital contribution, reactivity descriptor, Fukui function analysis of phthalimide derivatives. Molecular docking and ADMET prediction were also performed. Result: The phthalimide derivatives were subjected to molecular docking studies, and binding affinities ranging from -7.3 to -7.7 kcal/mol against PAK1 kinase were determined. The docked ligands demonstrated stronger hydrogen bonding, electrostatic interactions, and hydrophobic interactions with PAK1 kinase. The magnitude of these contacts usually related with bond lengths and attraction forces. The derivatives with an elevated docking score were chosen against ADMET in silico, and they have an excellent oral bioavailability without observed carcinogenesis or mutagenicity affect. Conclusion: These results reveal that these phthalimide derivatives might be potential inhibitors for the protein kinase PAK1.