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

Abstract

Molecular mechanics (MM) calculations such as a systematic sampling approach reported from Merck & Co., Inc. are usually 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. An auto-generation program of initial structures for DFT calculations using chemical structure search for common 3D fragments with SMARTS descriptions (ConfFragGeneration) was constructed. The initial structures of cholesteryl pelargonate for DFT calculations were automatically generated from the database of optimized population-rich conformations of cyclohexyl nonanoate and cholesteryl chloride by using the ConfFragGeneration program for the VCD analysis of the cholesteric liquid-crystal phase.