Computer calculations as an aid to drug design: more stable compounds related to thromboxane A2

Abstract

Semi-empirical SCF-MO calculations, mainly using the MNDO program, have been used to determine the smallest possible change that can be made to the bicyclic ring system of thromboxane A₂ in order to increase its stability. The bicyclic system 2,6-dioxabicyclo[3.1.1]heptane is predicted to be more stable with respect to its hydrolysis product when one or more oxygen atoms are replaced by sulphur, the order of stability being 2,6-dithiabicyclo[3.1.1]heptane > 2-oxa-6-thia analogue > 6-oxa-2-thia-analogue > 2,6-dioxabicyclo [3.1.1]heptane. These predictions are qualitatively in agreement with observations on the stability of synthetic monothia- and dithia-analogues of thromboxane A₂. The optimised geometries for these bicyclic systems imply a considerable flattening of the end of the six-membered ring that is remote from the bridge, but a consideration of n.m.r. data for a monothia-analogue suggests that the optimisation overestimated the extent of flattening of the six-membered ring.