title: Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach.
abstract: Oncogenic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) are the most frequently reported in association with various forms of cancer. Several studies have reported the significance of hotspot mutations in a catalytic subunit of PIK3CA in association with breast cancer. Mutations are frequently observed in the highly conserved region of the kinase domain (797-1068 amino acids) of PIK3CA are activating or gain-of-function mutations. Mutation in codon 1047 occurs in the C-terminal region of the kinase domain with histidine (H) replaced by arginine (R), lysine (L), and tyrosine (Y). Pathogenicity and protein stability predictors PhD-SNP, Align GVGD, HANSA, iStable, and MUpro classified H1047R as highly deleterious when compared to H1047L and H1047Y. To explore the inhibitory activity of Wortmannin toward PIK3CA, the three-dimensional structure of the mutant protein was determined using homology modeling followed by molecular docking and molecular dynamics analysis. Docking studies were performed for the three mutants and native with Wortmannin to measure the differences in their binding pattern. Comparative docking study revealed that H1047R-Wortmannin complex has a higher number of hydrogen bonds as well as the best binding affinity next to the native protein. Furthermore, 100 ns molecular dynamics simulation was initiated with the docked complexes to understand the various changes induced by the mutation. Though Wortmannin was found to nullify the effect of H1047R over the protein, further studies are required for designing a better compound. As SNPs are major genetic variations observed in disease condition, personalized medicine would provide enhanced drug therapy.
authors.affiliation: Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: D Thirumal
authors.initials: DT
authors.lastname: Kumar
authors.affiliation: Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India. Electronic address: georgecp77@yahoo.co.in.
authors.forename: C George Priya
authors.initials: CG
authors.lastname: Doss
mesh_terms: D000730:Androstadienes / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020134:Catalytic Domain; D058534:Class I Phosphatidylinositol 3-Kinases; D003062:Codon; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011485:Protein Binding; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D003062:Codon; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000077191:Wortmannin
keywords: Molecular docking; Molecular dynamics; PIK3CA; Personalized medicine; Single-nucleotide polymorphisms; Wortmannin