title: In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach.
abstract: A major challenge remaining in drug design efforts towards protein kinase is due to the development of drug resistance initiated by the missense mutations in the kinase catalytic domain. Gain or loss of function mutations in the REarranged during Transfection (RET) tyrosine kinase gene have been associated with the development of a wide range of human associated cancers and Hirschsprung's disease. However, to what extent these mutations might affect bio-molecular functions remains unclear. In this article, the functionally significant mutations in RET were screened with the aid of various sequence and structure based in silico prediction methods. We mapped the deleterious mutants, modelled mutant proteins and deciphered the impact of mutations on drug binding mechanisms in the RET crystal structure of PDB ID: with the potential inhibitor vandetanib by docking analysis. Furthermore, molecular dynamics simulations were undertaken to understand the mechanistic action of cancer associated mutations in altering the protein kinase structure, dynamics, and stability. According to our results, the overall effect of V804M, M918T and S922Y were destabilizing and mostly alter the electrostatic component of the binding energy. Specifically, the mutation of gatekeeper residue valine 804 present in the ATP binding pocket affects the protein stability and confers resistance to the drug vandetanib, which was consistent with previously published experimental results. Overall, our findings may provide useful structural insights for in-depth understanding of the molecular mechanism underlying RET mutation and developing effective drugs.
authors: Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India. georgepriyadoss@vit.ac.in georgecp77@yahoo.co.in.
authors: C
authors: C
authors: George Priya Doss
authors: B
authors: B
authors: Rajith
authors: Chiranjib
authors: C
authors: Chakraboty
authors: V
authors: V
authors: Balaji
authors: R
authors: R
authors: Magesh
authors: B
authors: B
authors: Gowthami
authors: Sneha
authors: S
authors: Menon
authors: M
authors: M
authors: Swati
authors: Manjari
authors: M
authors: Trivedi
authors: Jasmine
authors: J
authors: Paul
authors: Richa
authors: R
authors: Vasan
authors: Maitreya
authors: M
authors: Das
mesh_terms: D019943:Amino Acid Substitution; D003198:Computer Simulation; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics* / Q000494:pharmacology; D015203:Reproducibility of Results
chemical_list: D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret