Abstract
<jats:p>Cancer is a serious public health problem and is becoming more common, with a projected increase in deaths and more than 25 million new cases by 2050. A number of molecular mechanisms are involved in the tumoral process, one of which is never in mitosis A-related kinase 2 (NEK2), a serine/threonine protein kinase that is frequently amplified in various malignancies and is responsible for chromosomal instability, aneuploidy, and activation of several oncogenic pathways. Available kinase inhibitors are not yet optimized with respect to their pharmacokinetic properties for clinical use, and current therapies, including chemotherapeutic agents and immunotherapies, are often limited by drug resistance. In silico methods provide an efficient approach for identifying novel potent inhibitors prior to experimental testing, reducing both time and cost. In this study, an E-pharmacophore-based model and structure-based virtual screening were used to identify new inhibitors of NEK2. An energy-optimized pharmacophore model was employed to screen the Enamine REAL library containing millions of compounds. The top hits were evaluated for their pharmacodynamic and pharmacokinetic properties using ADMET profiling and were subsequently subjected to molecular docking using both standard precision and extra precision protocols. Three lead compounds (1, 2, and 3) were identified with docking scores of -7.414, -8.037, and -7.562, respectively. MM-GBSA calculations estimated binding free energies of -54.92, -54.18, and -49.23 kcal/mol for the corresponding complexes. Finally, 100 ns molecular dynamics simulations demonstrated the stability of the NEK2-ligand complexes under dynamic conditions. These findings suggest that the three identified compounds are promising NEK2 inhibitor candidates and warrant further validation through in vitro and in vivo studies for potential clinical application</jats:p>