PHARMACOPHORE BASED MODELLING OF PYRIDINE-PYRIMIDINE ANALOGS AS MER TYROSINE KINASES INHIBITORS IN ANTICANCER THERAPY

MER kinase is an important tyrosine-kinase receptor that is associated with a variety of cancers, including mantle cell lymphomas, pituitary adenomas and T-cell acute lymphoblastic leukemia. Identification of new MERTK inhibitors assumes crucial importance. Only one ligand-based pharmacophore model is reported to date for MERTK inhibitors. There are many more molecules with improved enzyme inhibitory activity reported since the publishing of this model. Because of this fact, we decided to develop a pharmacophore model for the MERTK inhibitors to assist in virtual screening using Phase for this purpose. Hydrogen bond donors, hydrogen bond acceptors, rings, positively ionizable groups, and hydrophobic groups were considered as key elements contributing to ligand activity for the pharmacophore model. Pharmacophore modelling was followed by extensive validation of the developed pharmacophore models. The developed pharmacophore model highlighted the importance of the positively ionizable groups and a ring structure. We have used these models for database screening to arrive at few hits. So findings in this study were proved to be useful in the optimization and discovery of MERTK inhibitors with a new scaffold.