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Molecular modulators of benzodiazepine receptor ligand binding
Author(s) -
Villar H. O.,
Loew G. H.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560360720
Subject(s) - steric effects , chemistry , substituent , affinities , ligand (biochemistry) , molecular recognition , stereochemistry , molecule , receptor , proton affinity , gabaa receptor , acceptor , organic chemistry , biochemistry , ion , protonation , physics , condensed matter physics
Ten derivatives of β‐carbolines with known affinities to the GABA A /BDZ (benzodiazepine) receptor were studied using the AM 1 and MNDO/H semiempirical techniques to identify and characterize molecular modulators of receptor recognition. Steric, lipophilic, and electrostatic properties of these compounds were calculated and examined for their possible role in recognition. Particular attention was paid to the regions around the two most favorable proton‐accepting sites, the βN and the substituent at the C 3 ‐ position, already implicated in recognition, as well as to the acidic N9H group that could be a proton‐donating center. To probe further the role of these three ligand sites in receptor interactions, a model of the receptor using three methanol molecules was made and optimum interactions of these three sites with them characterized. The results indicate some similarity in the shape of these ligands, which could reflect a steric requirement. The receptor affinity appears to be modulated to some extent by the ratio oflipophilic to hydrophilic surface, the negative potential at the βN, provided there is also one at the C 3 substituent confirming the importance of two accepting sites in recognition. The acidic N9H does not appear to be a modulator of affinity or does it form a stable H‐bond with methanol as acceptor. The two proton donating molecules do form such a stable complex, and both are needed for high affinity.