Identification of Novel Chemical Entities for Mirk/Dyrk1B Receptor Using Molecular Modeling and Molecular Dynamic Approaches

Abstract Cancer is a major health problem worldwide and one of the leading death-causing diseases. Mirk (Minibrain-related kinase is a member of the dual-specificity tyrosine-phosphorylation-regulated kinase (Dyrk) family that is highly upregulated in various solid tumors and mediates cell survival including lung cancer. Mirk effectively increases the expression of a series of antioxidant genes, which scavenge the reactive oxygen species and stabilize the p27kip1 that maintain the viability of the quiescent cancer cell and also mediates the cell cycle and survival of cancer cells by influencing the MAPK/ERK signaling pathway. Hence, Mirk acts as a novel therapeutic target for cancer prevention. Owing to the unavailability of the three-dimensional structure of Mirk, in the present study, we have modeled the 3D structure of Mirk, based on the crystal structure of Dyrk1a as a template, and subsequently used it as a target for virtual screening and molecular docking against a small molecule database. Based on the visual inspection, four best hits such as Chembridge_ID 7768949, 7771055, 7758866, and 7764195 have high binding affinity, good docking score, and pharmacokinetic properties were shortlisted. Further, the dynamic stability of lead molecules with modeled Mirk/Dyrk1B was evaluated using 10 ns molecular dynamics simulation approach. The four hit molecules exhibited good and stable binding complex in the binding pocket of the target protein. Collectively the finding of this study suggested that the identified molecules may serve as potential effective anti-cancer inhibitors for cancer prevention.