A Combined Molecular Docking and 3D‐QSAR Studies on Tetrahydropteridin Derivatives as PLK2 Antagonists

Abstract

Polo‐like kinase‐2 (PLK2) is a member of a highly conserved serine/threonine kinase family. PLK2 is implicated in the regulation of cell division. It is activated in the early G1 phase in cell cycle progression and is required for centriole duplication. It has been observed that the low expression of PLK2 leads to B‐cell lymphoma and ovarian cancer. Furthermore, it was found to be associated with poor prognosis in non‐small cell lung cancer, breast cancer, head and neck carcinoma, and osteosarcoma. Thus, PLK2 is considered as an important therapeutic target for cancer drug design due to its multiple roles in several types of cancers. In this work, molecular docking and 3D‐QSAR techniques were performed on tetrahydropteridin derivatives as PLK2 inhibitors. Docking study identified crucial active site residues such as Leu88, Cys96, Ala109, Lys111, Val143, Leu159, Glu160, Cys162, and Phe212 which helps in the firm binding of the ligand. Receptor‐guided CoMFA (q 2 = 0.859, NOC = 5, r 2 = 0.996) and CoMSIA (q 2 = 0.855, NOC = 6, r 2 = 0.998) models were produced. The predictability and stability of these models were assessed using different validation techniques. Contour maps revealed that electrostatic and steric substitutions were favorable at R1 and R2 positions respectively. In addition, the substitution of H‐bond donor group at the R1 position was also favored. The results of this study could be helpful for designing more potent PLK2 inhibitors.