IN-SILICO APPROACH TO DESIGN A NOVEL INHIBITOR OF SHP1/2:ENHANCEMENT OF HSCS PROLIFERATION

Abstract

Hematopoiesis is a lifelong process of the production and maintenance of all the cells of the blood system from the hematopoietic stem cells (HSCs) in a hierarchical manner. In adult mammals the hematopoietic stem cells (HSCs) reside in the bone marrow cavity. HSCs give rise to all the types of blood cells of the lymphoid and myeloid lineages. Radiation therapy in cancer leads to loss of a large number of immune cells, so HSCs are transplanted into the bone marrow of irradiated patients but HSCs differentiate before reaching the bone marrow, so the main aim is to maintain the HSCs in their proliferative state until they reach bone marrow. HSCs have three main characteristics of proliferation, self- renewal and differentiation. The proliferative property of HSCs is regulated by a number of signaling pathways, ligands and molecules, but one of the main regulators is the c-kit/SCF signaling. The binding of the SCF (Stem Cell Factor) to the c-kit receptor results in receptor dimerization, thereby activating c-kit activity. Src homology 2 (SH2) domain containing phosphatase 1 (SHP1) negatively regulates the c-kit activity. Hence in this work we have identified the structural variations using structural alignment between the PTPases and observed that HePTP is having high identity with SHP1. Based on this result we have screened known inhibitors of HePTP against SHP1 and identified some ligands having higher binding affinity than NSC87877. In order to design SHP1 specific inhibitor a pharmacophore model was designed to search for a NCE (Novel Chemical Entity).