Elucidating Binding Mechanisms of Pyrimidinone Derivatives at the Eg5 Kinesin Active Site: In Silico Drug Discovery Approach

Cancer has emerged as a rapidly escalating global health challenge in the modern world. According to World Health Organization estimates from 2020, cancer affects approximately one in six individuals and remains a leading cause of mortality worldwide. Factors such as metastasis, aggressive malignancy, limited cellular selectivity, lack of unified therapeutic strategies, late-stage detection, and costly treatments render cancer a major global health threat. The continued limitations of existing anticancer therapies necessitate sustained efforts toward the discovery of novel and potent therapeutic molecules. Traditional drug discovery is an expensive, complex, and time-consuming process; however, advances in computational drug discovery have transformed it into a more efficient, precise, and cost-effective paradigm. This study computationally evaluates newly reported pyrimidinone derivatives (G1 to G8) as potential inhibitors of Eg5 kinesin receptors, with comparative analysis against the standard inhibitor S-monastrol (G9). The Eg5 is a member of the kinesin family of motor proteins that plays a critical role in mitotic spindle assembly and chromosome segregation during cell division, and has therefore attracted significant research interest as a potential anticancer target. In addition, the drug-likeness properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles of all pyrimidinone derivatives were computationally evaluated. The binding affinities of all pyrimidinone derivatives toward the Eg5 kinesin receptor were evaluated and benchmarked against the standard. The results indicate that among the pyrimidinone derivatives, G5 exhibited the highest binding energy (−6.29 kJ/mol). This was followed by G4 and G2 derivatives ranked second and third, demonstrating binding energies of −6.03 and −5.90 kJ/mol, respectively, which are close to that of the standard G9. G5, G4, and G2 were advanced for molecular dynamics simulation studies based on their superior docking performance. Molecular dynamics simulations of 100 ns were performed for each Eg5 kinesin receptor–ligand complex (G5, G4, and G2) to gain deeper insights into their molecular-level interactions and stability. The molecular dynamics trajectories were analyzed using RMSD, RMSF, radius of gyration, and hydrogen bond formation parameters. The simulation trajectories exhibited good stability and remained within literature-reported acceptable limits. The MM/PBSA binding free energies of complex formation were calculated, yielding values of −13.80, −23.33, and −20.46 kcal/mol for the G2–Eg5, G4–Eg5, and G5–Eg5 complexes, respectively. Negative binding energy values indicate favorable and stable complex formation. The overall results of ADMET analysis, molecular docking, molecular dynamics simulations, and binding energy calculations suggest that the pyrimidinone derivatives are promising inhibitors of the Eg5 kinesin receptor.