Performance evaluation of flexible macrocycle docking in AutoDock

10 October 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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.

Keywords

docking
autodock
macrocycles

Supplementary materials

Title
Description
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Title
“Performance evaluation of flexible macrocycle docking in AutoDock (SUPPLEMENTARY MATERIAL)
Description
List of representative set of complexes containing macrocyclic ligands. List of complexes containing conformationally constrained macrocyclic peptides of therapeutic relevance
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Title
“Performance evaluation of flexible macrocycle docking in AutoDock (SUPPLEMENTARY MATERIAL)
Description
Coordinates of macrocycle complexes used in this study
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