Biological and Medicinal Chemistry

Performance evaluation of flexible macrocycle docking in AutoDock

Authors

Abstract

Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands flexibly, without requiring enumeration of macrocyclic conformers before docking. Here, we characterize the performance of the method for handling macrocyclic compounds, which is implemented and the default behavior for ligand preparation with our ligand preparation pipeline, Meeko. A pseudoatom is used to encode bond geometry and produce an anisotropic closure force for macrocyclic rings. This method is evaluated on a diverse set of small molecule and peptide macrocycles, ranging from 7- to 33-membered rings, showing little accuracy loss compared to rigid redocking of the x-ray macrocycle conformers. This suggests that for conformationally flexible macrocycles with unknown binding modes, this method can be effectively used to predict the macrocycle conformation.

Content

Thumbnail image of macrocycles_holcomb_v1.1.pdf

Supplementary material

Thumbnail image of macrocycles_holcomb_SI_v1.1.pdf
“Performance evaluation of flexible macrocycle docking in AutoDock (SUPPLEMENTARY MATERIAL)
List of representative set of complexes containing macrocyclic ligands. List of complexes containing conformationally constrained macrocyclic peptides of therapeutic relevance
Thumbnail image of macrocyclic_complexes.zip
“Performance evaluation of flexible macrocycle docking in AutoDock (SUPPLEMENTARY MATERIAL)
Coordinates of macrocycle complexes used in this study