Antagonist binding in the rat muscarinic receptor A study by docking and X-ray crystallography.

A series of agonists to the rat muscarinic receptor have been docked computationally to the active site of a homology model of rat M1 muscarinic receptor. The agonists were modelled on the X-ray crystal structure of atropine, which is reported here and the docking studies are shown to reproduce correctly the order of experimental binding affinities for the agonists as well as indicate where there appear to be inconsistencies in the experimental data. The crystal and molecular structure of atropine (tropine tropate; alpha-[hydroxymethyl]benzeneacetic acid 8-methyl[3.2.1]oct-3-yl ester C17H23NO3) has been determined by X-ray crystallography using an automated Patterson search method, and refined by full-matrix least-squares to a final R of 0.0452 for 2701 independent observed reflections and 192 parameters using Mo Kalpha radiation, lambda=0.71073A at 150K. The compound crystallises in space group Fdd2 with Z=16 molecules per unit cell.