Structure activity relationship of organic nitrates: an exploratory hypothesis via molecular models

Abstract

An exploratory attempt to explain the structure/activity relationship of organic nitrates was initiated. In addition to the partition coefficient, a new empirical parameter, F(5.8Å), was used in this correlation. This new parameter denotes the number of times that two oxygen atoms in the molecule can be arranged at a distance of 5.8Å. Vasodilating potencies (EC 50s) and partition coefficients of 11 organic nitrates were obtained from a literature report, while their corresponding F(5.8Å) values were obtained from manual determination using two molecular models, viz: CPK and Drieding. Via linear regression comparisons, we showed that F(5.8Å) was a better physicochemical parameter than the partition coefficient in explaining the differences in the observed pharmacologic activity. When the two parameters were combined, >90% of the variability of the potency was accounted for. These results suggest that the pertinent protein (most likely the activating enzyme) for organic nitrate activity may contain at least two ‘oxygen-philic’ attachment sites which are separated by a distance of 5.8Å.