Computational and Structure-Guided E-Pharmacophore-Based Virtual Screening for the Identification of Novel NEK2 Kinase Inhibitors as Potential Anticancer Agents

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 in coming decades. A number of molecular mechanisms are involved in the tumoral process, with one of them, never in mitosis A–related kinase 2 (NEK2), a serine/threonine protein kinase, being a frequent target of amplification in various malignancies that is responsible for chromosomal instability, aneuploidy and activation of several oncogenic pathways. Available kinase inhibitors are not yet optimized in terms of their pharmacokinetic properties for clinical use, and current therapies, such as chemotherapeutic agents or immunotherapies are often limited by their resistance. In silico methods represent an effective tool to search for novel potent inhibitors, before testing in animals, with time constraints and limited resources. To find new inhibitors of NEK2, we used E pharmacophore–based modeling and structure based virtual screening in this study. NEK2 was chosen as the target for therapeutic intervention and an energy optimized pharmacophore model was employed to screen the Enamine REAL library of millions of compounds. Pharmacodynamic and Pharmacokinetic properties of the Top hits were tested using ADMET profiling. These were further screened using molecular docking (standard precision and extra precision) and virtual screening to obtain three lead compounds 1, 2, and 3 which have docking score of −7.414, −8.037 and −7.562 respectively. MM-GBSA calculations were used to estimate the binding free energies for these complexes, which were determined to be −54.92, −54.18 and −49.23 kcal/mol. Lastly, 100 ns molecular dynamics simulations have been run to evaluate complex stability in dynamic situations. The overall results of the MD showed the overall stability of the NEK2–ligand complexes, and thus these three compounds are promising NEK2 inhibitor candidates and could be further validated in vitro and in vivo for clinical application.