A 3D QSAR analysis of in vitro binding affinity and selectivity of 3-isoxazolylsulfonylaminothiophenes as endothelin receptor antagonists

Comparative molecular field analysis (CoMFA) was used to generate 3D QSAR models for endothelin receptor-A (ET(A)) binding affinity and ET(A) vs. ET(B) selectivity. A diverse set of 106 novel 3-isoxazolylsulfonylaminothiophene compounds were selected for this study. These compounds are among the most potent ET(A)-selective antagonists reported. The models possessed promising predictive ability as indicated by the high cross-validated correlation and the prediction on the external test set. The analyses showed that steric and electrostatic interactions contributed equally to ET(A) binding affinity and selectivity. The hydrogen-bond acceptor nature of the carbonyl group in the linker was essential for both properties. In addition, regions around the extended phenyl ring were explored and optimizations were proposed. The steric interactions around the ortho-position of the phenyl ring might improve both properties, while that around the para-position would influence only the affinity. Along with the CoMFA analyses, the bioactive conformation of the compounds in which two structural moieties tethered by the sulfonamide bond appeared to interact strongly with each other was proposed.