Abstract:
:We have derived a model of the nicotinic acetylcholine binding site. This was accomplished by using three known agonists (acetylcholine, nicotine and epibatidine) as templates around which polypeptide side chains, found to be part of the receptor cavity from published molecular biology studies, are allowed to flow freely in molecular dynamics simulations and mold themselves around these templates. The resulting supramolecular complex should thus be a complement, both in terms of steric effects as well as electronic effects, to the agonists and it should be a good estimation of the true receptor cavity structure. The shapes of those minireceptor cavities equilibrated rapidly on the simulation time scale and their structural congruence is very high, implying that a satisfactory model of the nicotinic acetylcholine binding site has been achieved. The computational methodology was internally tested against two rigid and specific antagonists (dihydro-beta-erytroidine and erysoidine), that are expected to give rise to a somewhat differently shaped binding site compared to that derived from the agonists. Using these antagonists as templates there were structural reorganizations of the initial receptor cavities leading to distinctly different cavities compared to agonists. This indicates that adequate times and temperatures were used in our computational protocols to achieve equilibrium structures for the agonists. Overall, both minireceptor geometries for agonists and antagonists are similar with the exception of one amino acid (ARG209).
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Gálvez-Ruano E,Iriepa-Canalda I,Morreale A,Lipkowitz KBdoi
10.1023/a:1008029924865subject
Has Abstractpub_date
1999-01-01 00:00:00pages
57-68issue
1eissn
0920-654Xissn
1573-4951journal_volume
13pub_type
杂志文章abstract::The "embedded cluster reference interaction site model" (EC-RISM) integral equation theory is applied to the problem of predicting aqueous pKa values for drug-like molecules based on an ensemble of tautomers. EC-RISM is based on self-consistent calculations of a solute's electronic structure and the distribution funct...
journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-011-9458-5
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-017-0069-7
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000021834.50768.c6
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-013-9665-3
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journal_title:Journal of computer-aided molecular design
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doi:10.1023/a:1027347527385
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00135313
更新日期:1991-12-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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更新日期:2008-06-01 00:00:00
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doi:10.1007/s10822-020-00287-0
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-013-9663-5
更新日期:2013-06-01 00:00:00
abstract::Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein-ligand binding. Different cl...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9757-8
更新日期:2014-07-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00124460
更新日期:1996-02-01 00:00:00
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1022479510524
更新日期:2002-10-01 00:00:00
abstract::Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resultin...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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