IDENTIFICATION OF THE MOTILIDE PHARMACOPHORES USING QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS

Erythromycin A and some derivatives have been shown to act as agonists at the motilin receptor site (motilides) and a structural similarity between these molecules and the N-terminal fragment of motilin has bee n proposed. Conformational analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been used to d etermine the homology between a series of erythromycin A derivatives a nd motilin 1-10. A total of 18 compounds has been studied to correlate the gastrointestinal motor stimulating (GMS) activity with the struct ure-related parameters determined by 3D-QSAR. Two models with good pre dictive power of the GMS activity are presented, leading to the predic tion of motilin 1-10 activity. The models are consistent with the majo rity of the data available. The most significant parameters for GMS ac tivity are a favorable dispersion interaction from the quaternary ammo nium group of the desosamine ring. In motilin 1-10, the aromatic side chains of Phe(1) and Tyr(7) seem to play the same role as the quaterna ry ammonium group in models I and 2, respectively. Some hydroxyl group s of erythromycin A derivatives and hydrophobic groups of the Val(2) a nd Ile(4) side chains of motilin also contribute to the GMS activity. The experimental GMS activities measured are in good agreement with th e predicted values, with correlation coefficient Values of 0.98 and 0. 94 in models 1 and 2, respectively.