Understanding channel blocking in the nicotinic acetylcholine receptor

Ion-channel blockers are molecules that obstruct the path used by ions to c ross the membrane through a protein channel. Many of these are local anesth etics, toxins or drugs of abuse, and the knowledge of their mechanism of ac tion at the atomic level is an important step towards the development of ne w compounds on a structural basis. A molecular model of the transmembrane r egion of the nicotinic acetylcholine receptor, an important brain and muscl e fast signaling protein, was used as a target for docking several channel blockers by means of an automatic docking method. The combination of the in dependent docking method and molecular models (of the receptor and blockers ) reproduced or explained quite accurately experimental data (photoaffinity labeling, site-directed mutagenesis, binding assays). This represents a st rong support for the validity of the predictions made for those molecules f or which no experimental data is available and also for the models and meth ods on which are based.