Stochastic approach to force field evaluations: conformational analysis of raloxifene, a potential new therapeutic agent for post-menopausal osteoporosis

Abstract

Three widely used force fields are compared with regard to their ability to describe conformer populations. The test molecule is raloxifene, an exciting new potential medicine for treating postmenopausal osteoporosis in women. The TRIPOS (Sybyl), MM3, and UFF force fields are used to sample the low energy conformations of the long piperidinium-containing side chain of this selective estrogen receptor modulator. In this test, the conformer populations are particularly affected by nonbonded interactions. MM3 gives reasonable results, as does the UFF force field, although the latter is sensitive to the setup of a conformational search calculation. The TRIPOS (Sybyl) force field overestimates nonbonded attractions, thus biasing the conformer population toward folded structures in which the cationic ring abuts the phenolic ring.