Evaluation of influence of single nucleotide polymorphisms in cytochrome P450 2B6 on substrate recognition using computational docking and molecular dynamics simulation

PLoS One. 2014 May 5;9(5):e96789. doi: 10.1371/journal.pone.0096789. eCollection 2014.

Abstract

In this study, we investigated the influence of single nucleotide polymorphisms on the conformation of mutated cytochrome P450 (CYP) 2B6 proteins using molecular dynamics (MD) simulation. Some of these mutations influence drug metabolism activities, leading to individual variations in drug efficacy and pharmacokinetics. Using computational docking, we predicted the structure of the complex between the antimalarial agent artemether and CYP2B6 whose conformations were obtained by MD simulation. The simulation demonstrated that the entire structure of the protein changes even when a single residue is mutated. Moreover, the structural flexibility is affected by the mutations and it may influence the enzyme activity. The results suggest that some of the inactive mutants cannot recognize artemether due to structural changes caused by the mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Artemether
  • Artemisinins / chemistry
  • Cytochrome P-450 CYP2B6 / chemistry
  • Cytochrome P-450 CYP2B6 / genetics*
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Models, Chemical
  • Molecular Dynamics Simulation
  • Mutation
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • Protein Structure, Secondary
  • Substrate Specificity
  • Temperature

Substances

  • Artemisinins
  • Ligands
  • Artemether
  • Cytochrome P-450 CYP2B6

Grants and funding

This work was supported by a grant-in-aid for scientific research (23790137) from the Japan Society for the Promotion of Science(http://www.jsps.go.jp/english/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.