期刊
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
卷 25, 期 8, 页码 709-716出版社
SPRINGER
DOI: 10.1007/s10822-011-9453-x
关键词
alpha-Cyclodextrin; Conformational flexibility; Drug design; DNA-ligand binding; Molecular dynamics
资金
- National Centre of Competence in Research (NCCR) in Structural Biology
- Swiss National Science Foundation (SNSF) [200020-121913]
- European Research Council (ERC) [228076]
- Spanish MEC/FEDER [BIO2007-62954]
- Slovenian Research Agency (ARRS) [Z1-9576]
- ICREA Funding Source: Custom
Docking algorithms for computer-aided drug discovery and design often ignore or restrain the flexibility of the receptor, which may lead to a loss of accuracy of the relative free enthalpies of binding. In order to evaluate the contribution of receptor flexibility to relative binding free enthalpies, two host-guest systems have been examined: inclusion complexes of alpha-cyclodextrin (alpha CD) with 1-chlorobenzene (ClBn), 1-bromobenzene (BrBn) and toluene (MeBn), and complexes of DNA with the minor-groove binding ligands netropsin (Net) and distamycin (Dist). Molecular dynamics simulations and free energy calculations reveal that restraining of the flexibility of the receptor can have a significant influence on the estimated relative ligand-receptor binding affinities as well as on the predicted structures of the biomolecular complexes. The influence is particularly pronounced in the case of flexible receptors such as DNA, where a 50% contribution of DNA flexibility towards the relative ligand-DNA binding affinities is observed. The differences in the free enthalpy of binding do not arise only from the changes in ligand-DNA interactions but also from changes in ligand-solvent interactions as well as from the loss of DNA configurational entropy upon restraining.
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