Prospective identification of biologically active structures by topomer shape similarity searching

The principle of bioisosterism-similarly shaped molecules are more likely t o share biological properties than are other molecules-has long helped to g uide drug discovery. An algorithmic implementation of this principle, based on shape comparisons of a single rule-generated "topomer" conformation per molecule, had been found to be the descriptor most consistently predictive of similar biological properties, in retrospective studies, and also to be well-suited for searching large (>10(12)) "virtual libraries" of potential reaction products. Therefore a prospective trial of this shape similarity searching method was carried out, with synthesis of 425 compounds and testi ng of them for inhibition of binding of angiotensin II (A-II). The 63 compo unds that were identified by shape searching as most similar to any of four query structures included all of the seven compounds found to be highly ac tive, with none of the other 362 structures being highly active (p < 0.001) . Additional consistent relations (p < 0.05) were found, among all 425 comp ounds, between the degree of shape similarity to the nearest query structur e and the frequency of various levels of observed activity. Known "SAR" (ru les specifying structural features required for A-II antagonism) were also regenerated within the biological data for the 63 shape similar structures.