Discovery of a New Dihydropyrimidinone Derivative as a Potential Haspin Kinase Inhibitor: Structure‐Guided Insights, In‐Vitro and Molecular Dynamics‐Based Validation

Abstract

AbstractStructure‐based virtual screening is efficient method for finding novel scaffolds/molecules for biological targets. Due to the accessibility of the Haspin crystal structure and its prevalence in various diseases; we sought exploring novel Haspin kinase inhibitors. We used the commercially available Chembridge library for virtual screening which had nearly 7,00,000 compounds. We employed variety of computational tools such as molecular docking, molecular dynamics simulations, in silico pharmacokinetics analysis to identify novel inhibitors targeting Haspin kinase. Based on chemical features, docking score, and MMGB/SA binding strength, 10 ligands were chosen. On in vitro determination, one chemical entity was found to inhibit Haspin's enzyme function at 72 % at 10 μM. Compound 16503395 had higher selectivity over Haspin kinase activity than the other kinases. The IC50 value for the compound 16503395 that inhibits Haspin kinase significantly was determined and was found to be 2.6 μM. After subjecting to molecular dynamics simulation analysis for compound 16503395 Haspin protein complex, we found that the Haspin kinase binding site amino acid unique residues Gly608, Glu492, Lys511, Asn654, Asp687, Ala503, Leu656 and Phe605 play important role in binding kinetics. We claim 5‐(hydroxymethyl)‐N‐[cis‐3‐(6‐oxo‐2‐pyrrolidin‐1‐yl‐1,6‐dihydropyrimidin‐4‐yl)cyclobutyl]‐2‐furamide (16503395) as a selective and potential Haspin kinase inhibitor.