Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

Abstract

Nek6 is a member of the NIMA (never in mitosis, gene A)-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602) were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

Assessment of dual inhibitory activity of epifriedelanol isolated from <i>Cayratia trifolia</i> against ovarian cancer

“…The force field is used for the docking protocol is OPLS_2005. The lowest-energy docked complexes were found in the majority of similar docking conformations (Srinivasan et al, 2014).…”

In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the Nek family of kinases

“…76 Nek6 is also upregulated in a wide range of malignancies, including breast cancer, colon cancer, lung cancer, gastric cancer, melanoma, non-Hodgkins lymphoma, and glioblastoma. [77][78][79] Although there has been one report on virtual screening for Nek6, 80 and one report on a thermal shift assay for several Nek6 variants, 81 no potent Nek6 scaffolds have emerged. Perhaps the most promising Nek6 chemical starting point at present is an ATM inhibitor, compound 27g from St. Jude (Fig.…”

Analysis of Novel C-X-C Chemokine Receptor Type 4 (CXCR4) Inhibitors from Hexane Extract of Euclea crispa (Thunb.) Leaves by Chemical Fingerprint Identification and Molecular Docking Analysis

“…Thus, CXCR4 active site residues were picked to generate grid in the centroid of these residues for molecular docking approach. 18 Among the identifed 25 bioactive compounds from the E. crispa leaves extract, SCHEMBL15979821, Hydrocortisone Acetat and Phenyl Glucuronide has better binding affinity with CXCR4 when compared with other compounds and these compounds may lead to develop an novel therapeutic agents. ADME properties of screened compounds do not predict any adverse effect that could be implicated in the failure of drugs.…”