Interaction of antagonists with calmodulin: insights from molecular dynamics simulations.
Article Details
- CitationCopy to clipboard
Kovesi I, Menyhard DK, Laberge M, Fidy J
Interaction of antagonists with calmodulin: insights from molecular dynamics simulations.
J Med Chem. 2008 Jun 12;51(11):3081-93. doi: 10.1021/jm701406e. Epub 2008 Apr 15.
- PubMed ID
- 18459732 [ View in PubMed]
- Abstract
We report results of 12 ns, all-atom molecular dynamics simulation (MDS) and Poisson-Boltzmann free energy calculations (PBFE) on calmodulin (CaM) bound to two molecules of trifluoperazine (TFP) and of N-(3,3, diphenylpropyl)- N'-[1- R-(3,4-bis-butoxyphenyl)-ethyl]-propylenediamine (DPD). X-ray data show very similar structures for the two complexes, yet the antagonists significantly differ with respect to their CaM binding affinities, the neutral DPD is much more potent. The goal of the study was to unravel the reason why TFP is less potent although its positive charge should facilitate binding. The electrostatic energy terms in CHARMM and binding free energy terms of the PBFE approach showed TFP a better antagonist, while inspection of hydrophobic contacts supports DPD binding. Detailed inspection of the amino acid contributions of PBFE calculations unravel that steric reasons oppose the favorable binding of TFP. Structural conditions are given for a successful drug design strategy, which may benefit also from charge-charge interactions.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Trifluoperazine Calmodulin Kd (nM) 1000 N/A N/A Details