GLIMPSED: An Improved Docking Protocol for Cognate Docking

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Glide SP is a standard molecular docking protocol.
• Binding site characteristics can influence docking accuracy.
• Ligand pose prediction is crucial for virtual screening.

Purpose of the Study:

• To evaluate and improve the cognate docking performance of Glide.
• To develop a protocol that accounts for binding site exposure.
• To enhance the accuracy of ligand pose prediction in molecular docking.

Main Methods:

• Utilized the Astex diverse set for docking performance evaluation.
• Developed GLIMPSED protocol, adapting Glide SP based on SiteMap binding site exposure.
• Employed MM-GBSA rescoring for solvent-exposed binding sites.
• Compared GLIMPSED and Glide SP using Hawkins et al. metrics.

Main Results:

• Standard Glide SP achieved an 85.7% success rate.
• GLIMPSED achieved an 89.3% success rate, a statistically significant improvement.
• SiteMap binding site exposure was identified as a key parameter for protocol selection.
• Cohen's effect size test indicated a small but non-trivial superiority for GLIMPSED.

Conclusions:

• The SiteMap binding site exposure parameter is a valuable guideline for choosing docking protocols.
• GLIMPSED offers enhanced accuracy in predicting ligand binding poses, especially for solvent-exposed sites.
• The findings support the adoption of adaptive docking strategies in drug discovery.