In Silico Profiling and Structural Insights of K634A and T681A, I, F, M Mutations in the 3D-Structure of PDGFR-β by Molecular Modeling and Molecular Dynamics Approach

Human Platelet Derived Growth Factor Receptor - Beta (PDGFR-β) belongs to the Receptor Tyrosine Kinases family - III that share structure similarity with other members i.e PDGFR-α, CSF, Fms, Flt3 and Kit. In human glioblastoma PDGFR-α is expressed by tumor cells while PDGFR-β expression is correlated with endothelial cells of tumor-associated blood vessels regulates primarily in early hematopoiesis. PDGFR-β is a novel therapeutic target for glioblastoma (GBM). However, a major challenge of GBM therapy is to overcome drug resistance due to mutations in the protein kinase catalytic domain limits the therapeutic effects of inhibitors. The present work mainly focused around the computational structural insight on PDGFR-β wild-type (WT) and mutant type (MT) to reveal the probable mechanism of resistance relevant to anti-angiogenic and anticancer drug sunitinib. Due to the absence of crystal structure, the 3D structure of PDGFR-β kinase domain (WT) and (MT) were predicted using comparative modeling followed by molecular docking analysis with sunitinib. The molecular dynamic simulations of PDGFR-β (WT) and (MT) with sunitinib were commenced to disclose the differential structural alterations in the PDGFR-β structure, dynamics, and its stability. The result showed that the overall mutational affect on the residues K634A, T681M, T681F, T681I, and T681A led to perturbed the 3D structure of PDGFR-β and altered the binding energy with sunitinib. Specifically, the mutation at gatekeeper residue threonine (T681M), present in the ATP binding site, triggered the significant conformational modulations, led to decrease in binding affinity of sunitinib (ΔG = -5.80 Kcal mol-1; Ki = 55.75 μM) as compare to WT (ΔG = -12.94 Kcal mol-1; Ki = 0.32 nM) respectively, thus conferring the resistance to the drug sunitinib. Present findings markedly displayed that the molecular interactions of sunitinib with PDGFR-β structure (WT and MT) leads to differential binding causing the development of resistance to sunitinib chemotherapy.