Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular modeling

Background:

• Macrocyclic compounds are increasingly important in drug discovery.
• Docking large, flexible macrocycles presents computational challenges.
• Standard docking protocols may not be optimal for macrocycle conformation.

Purpose of the Study:

• To evaluate and compare different computational docking protocols for macrocyclic compounds.
• To determine the most accurate and efficient method for macrocycle-ligand docking.
• To assess the performance of Glide flexible docking against rigid docking methods.

Main Methods:

• Assembled screening and validation sets of macrocycle-protein complexes from the Protein Data Bank (PDB).
• Docked macrocycles using Glide flexible docking with ring-templating.
• Compared Glide flexible docking with rigid docking of pregenerated conformational ensembles from Macrocycle Conformational Sampling (MCS) and Monte Carlo Multiple Minimum (MCMM) searches.
• Evaluated docking accuracy using Root Mean Square Deviation (RMSD) against X-ray structures.

Main Results:

• Glide flexible docking achieved a median RMSD of 0.58 Å for top-scored poses on the screening set.
• No significant difference in accuracy was found between Glide flexible docking and rigid docking of MCS-generated conformations.
• Glide flexible docking was twice as fast as the MCS protocol for the screening set.
• The new Prime-MCS method was faster than MCS but generated suboptimal conformations for rigid docking.

Conclusions:

• Standard Glide flexible docking with prior ring-templating is recommended for docking macrocycles.
• This protocol offers a superior balance of speed, accuracy, and ease of setup compared to existing gold-standard rigid docking protocols.
• The findings provide valuable guidance for computational drug discovery efforts involving macrocyclic compounds.