Construction of a ring structure-enabled auto-generation program of initial structures using chemical structure search for 3D fragments

Abstract

Molecular mechanics (MM) calculations in such a systematic sampling approach reported from Merck & Co., Inc. have usually been used for conformational search. However, in a collaborative study with a Japanese pharmaceutical company, we found that the predicted vibrational circular dichroism (VCD) spectra of more than 30% of pharmaceutical candidates, where the spectra were predicted using routine procedures, could not reproduce the observed spectra; in addition, several population-rich conformations predicted using density functional theory (DFT) calculations were missed by routine conformational searches with MM calculations. A ring structure-enabled auto-generation program of initial structures for DFT calculations (RingFragGeneration) using chemical structure search for three dimensional (3D) fragments represented as maximal common substructures (MCSs) was constructed. Initial structures of rapamycin for DFT calculations were automatically generated from the database of op timized population-rich conformations of fragment molecules by using this program for VCD analysis of the macrolide ring with 49 rotatable single bonds.