Improving Conformer Generation for Small Rings and Macrocycles Based on Distance Geometry and Experimental Torsional-Angle Preferences.

ABSTRACT

The conformer generator ETKDG is a stochastic search method that utilizes distance geometry together with knowledge derived from experimental crystal structures. It has been shown to generate good conformers for acyclic, flexible molecules. This work builds on ETKDG to improve conformer generation of molecules containing small or large aliphatic (i.e., non-aromatic) rings. For one, we devise additional torsional-angle potentials to describe small aliphatic rings and adapt the previously developed potentials for acyclic bonds to facilitate the sampling of macrocycles. However, due to the larger number of degrees of freedom of macrocycles, the conformational space to sample is much broader than for small molecules, creating a challenge for conformer generators. We therefore introduce different heuristics to restrict the search space of macrocycles and bias the sampling toward more experimentally relevant structures. Specifically, we show the usage of elliptical geometry and customizable Coulombic interactions as heuristics. The performance of the improved ETKDG is demonstrated on test sets of diverse macrocycles and cyclic peptides. The code developed here will be incorporated into the 2020.03 release of the open-source cheminformatics library RDKit.