Docking of 1,4-Benzodiazepines in the 1/ 2 GABAA Receptor Modulator Site

Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
Molecular pharmacology (Impact Factor: 4.13). 06/2009; 76(2):440-50. DOI: 10.1124/mol.109.054650
Source: PubMed


Positive allosteric modulation of the GABA(A) receptor (GABA(A)R) via the benzodiazepine recognition site is the mechanism whereby diverse chemical classes of therapeutic agents act to reduce anxiety, induce and maintain sleep, reduce seizures, and induce conscious sedation. The binding of such therapeutic agents to this allosteric modulatory site increases the affinity of GABA for the agonist recognition site. A major unanswered question, however, relates to how positive allosteric modulators dock in the 1,4-benzodiazepine (BZD) recognition site. In the present study, the X-ray structure of an acetylcholine binding protein from the snail Lymnea stagnalis and the results from site-directed affinity-labeling studies were used as the basis for modeling of the BZD binding pocket at the alpha(1)/gamma(2) subunit interface. A tethered BZD was introduced into the binding pocket, and molecular simulations were carried out to yield a set of candidate orientations of the BZD ligand in the binding pocket. Candidate orientations were refined based on known structure-activity and stereospecificity characteristics of BZDs and the impact of the alpha(1)H101R mutation. Results favor a model in which the BZD molecule is oriented such that the C5-phenyl substituent extends approximately parallel to the plane of the membrane rather than parallel to the ion channel. Application of this computational modeling strategy, which integrates site-directed affinity labeling with structure-activity knowledge to create a molecular model of the docking of active ligands in the binding pocket, may provide a basis for the design of more selective GABA(A)R modulators with enhanced therapeutic potential.

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Available from: David H Farb, Apr 17, 2014
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    • "So far, drug discovery efforts have relied mainly on indirect structural insight from focused [8]–[12] or unified pharmacophore models recapitulating the structure-activity relationships (SAR) of compounds synthesized during more than fifty years of active medicinal chemistry research in the field [13], [14]. Homology models, on the other hand, have had little practical impact on the design process despite a number of models reported in the literature [15]–[25]. The models were mainly built using the homologous acetylcholine binding proteins (AChBPs) as templates. "
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