QSAR, PHARMACOPHORE FEATURES AND MOLECULAR DOCKING STUDY OF PIRAZOLO-[3,4-D]-PYRIMIDINES AS MER TYROSINE KINASE INHIBITOR

• Main Author: Hamzah, Nursalam
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/79068
• Institution: Institut Teknologi Bandung

Mer receptor tyrosine kinase is ectopically expressed in Acute Lymphoblastic Leukemia (ALL) cell lines, but Mer is not expressed in normal mouse and human T and B-lymphocytes at any stage of development. Inhibition of Mer expression reduces pro-survival signaling, dramatically increases the sensitivity of leukemia cells to cytotoxic agents, and thus significantly delays development of leukemia. Pirazolo-[3,4-d]-pyrimidine is a new-generation drug which acts as an inhibitor of the Mer tyrosine kinase. The aim of present research are to know the predictors that influence of activity of Mer receptor tyrosine kinase inhibitor and to determine the best QSAR equation that showed the quantitative structure and activity relationship of pirazolo-[3,4-d]-pyrimidines, determine pharmacophore features which play a role in binding to the receptor and to design new derivative of pirazolo-[3,4-d]-pyrimidine derivatives which are expected to have higher activity and selectivity. Evaluation of the interaction between new designed derivatives and Mer receptor tyrosine kinase is also the object of the present study. Modeling and geometry optimization of molecular structure were calculated by HyperChem 8.0. In which, geometry optimization was performed by Ab initio method. QSAR descriptor were calculated using MOE 2009, while statistical analysis was evaluated by multilinear regression analysis using SPSS Statistics 17. Leave On Out cross validation techniques was applied to obtain the QSAR equation with significance statistical criteria. Pharmacophore model was created using the ‘Pharmacophore Query Editor’and was applied for interaction vii study between ligand and protein receptor. Molecular docking for studying the ligand-receptor interactions was also performed by MOE. The QSAR model suggests that steric parameters such as molecular refractivity and van der Waals volume are crucial for the inhibitory activity. In addition, ASA_H, log S and energy of the LUMO positively contribute to the Mer inhibition. The pharmacophore model of Mer inhibitors suggests that one aromatic, one ionic interaction and four H-bonding play important roles in Mer inhibitors. Novel compounds were designed by modifying substituent in order to obtain the fit pharmacophores features and considering descriptor of the best QSAR equation model. There are ten novel compounds of pirazolo-[3,4-d]-pyrimidine derivatives which have a theoretical activity better than its parent compound. The most active compound has a good docking score, and has ability to interact with binding site of Mer receptor tyrosine kinase.