Computational analysis revealing that K634 and T681 mutations modulate the 3D-structure of PDGFR-β and lead to sunitinib resistance

Abstract

Platelet-derived growth factor receptor-beta (PDGFR-β) is expressed by endothelial cells (ECs) of tumor-associated blood vessels and regulates primarily early hematopoiesis. Human PDGFR-β is a novel therapeutic target for the treatment of glioblastoma. However, a major challenge of glioblastoma therapy is to overcome drug resistance, mostly initiated by missense mutations in the protein kinase catalytic domain. The present work aimed to carry out in silico structural studies on wild-type (WT) and some major mutant-type (MT) PDGFR-β complexes to elucidate the probable mechanism of its resistance related to the anti-angiogenic and anticancer drug sunitinib. In the absence of a crystal structure, the 3D structures of WT and MT PDGFR-β kinase were predicted using homology modeling followed by docking analysis with sunitinib. Molecular dynamics simulations of WT and MT PDGFR-β complexes with sunitinib were performed to understand the differential structural alterations in the PDGFR-β kinase structure, as well as its stability. Our results showed that the overall effect of mutations in the residues K634A, T681M, T681F, T681I, and T681A led to the destabilized 3D structures of PDGFR-β and altered their binding affinities with sunitinib. In particular, the mutation at the gatekeeper residue threonine 681 (T681M), present in the ATP binding pocket, majorly affected the protein stability, thus conferring resistance to the drug sunitinib. Our present findings utilizing in silico approaches show that the differential binding of sunitinib with WT and MT proteins leads to resistance being developed in sunitinib chemotherapy.