Molecular modelling of asperlicin derived cholecystokinin A receptor antagonists.
The C3-substituted benzodiazepines derived from asperlicin, e.g. devazepide (L-364,718, MK-329), constitute the most potent class of cholecystokinin A-type (CCKA) receptor antagonists. In order to gain insight into the prerequisites for binding, we examined the conformational properties of both potent and weak representatives of this class with computer assisted molecular modelling (CAMM) techniques. The CAMM results indicate that the binding site for the C3-substituents is a planar slot on the CCKA receptor surface and, in addition, allow the proposal of a model which describes the relative binding mode of the less potent R isomers versus that of the S isomers. The latter model illustrates the unique spatial properties of the benzodiazepine moiety, which we suggest functions primarily as an invertible core which assures an optimal arrangement of attached substituents.
Van der Bent
A
A
Division of Medicinal Chemistry, Center for Bio-Pharmaceutical Sciences, Leiden, Netherlands.
Ter Laak
A M
AM
IJzerman
A P
AP
Soudijn
W
W
D001570:Benzodiazepinones / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D020109:Devazepide; D008958:Models, Molecular; D008968:Molecular Conformation; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D001570:Benzodiazepinones; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; D020109:Devazepide; C046367:asperlicin