Discovery of potent NEK2 inhibitors as potential anticancer agents using structure-based exploration of NEK2 pharmacophoric space coupled with QSAR analyses.
High expression of Nek2 has been detected in several types of cancer and it represents a novel target for human cancer. In the current study, structure-based pharmacophore modeling combined with multiple linear regression (MLR)-based QSAR analyses was applied to disclose the structural requirements for NEK2 inhibition. Generated pharmacophoric models were initially validated with receiver operating characteristic (ROC) curve, and optimum models were subsequently implemented in QSAR modeling with other physiochemical descriptors. QSAR-selected models were implied as 3D search filters to mine the National Cancer Institute (NCI) database for novel NEK2 inhibitors, whereas the associated QSAR model prioritized the bioactivities of captured hits for in vitro evaluation. Experimental validation identified several potent NEK2 inhibitors of novel structural scaffolds. The most potent captured hit exhibited an [Formula: see text] value of 237 nM.
Department of Pharmaceutical sciences, Faculty of Pharmacy, The University of Jordan, P.O. Box 13140, Amman, 11942, Jordan. m_khanfar@ju.edu.jo.|Institut fuer Pharmazeutische and Medizinische Chemie, Heinrich-Heine-Universitaet Duesseldorf, 40225, Duesseldorf, Germany. m_khanfar@ju.edu.jo.
Mohammad A
MA
Khanfar
Department of Pharmaceutical sciences, Faculty of Pharmacy, The University of Jordan, P.O. Box 13140, Amman, 11942, Jordan.
Fahmy
F
Banat
Department of Pharmaceutical sciences, Faculty of Pharmacy, The University of Jordan, P.O. Box 13140, Amman, 11942, Jordan.
Shada
S
Alabed
Department of Pharmaceutical sciences, Faculty of Pharmacy, The University of Jordan, P.O. Box 13140, Amman, 11942, Jordan.
Saja
S
Alqtaishat
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D000072379:NIMA-Related Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000072379:NIMA-Related Kinases
NEK2; Pharmacophore; QSAR; cancer