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A New Method for Navigating Optimal Direction for Pulling Ligand from Binding Pocket: Application to Ranking Binding

Quan Van Vuong¹, Tin Trung Nguyen¹, Mai Suan Li^1,2

¹Institute for Computational Science and Technology, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.

Journal of Chemical Information and Modeling

|November 24, 2015

Summary

We developed Minimal Steric Hindrance (MSH), a new method for ligand-receptor binding analysis. MSH accurately predicts binding free energies by considering ligand geometry, outperforming existing methods like CAVER.

Area of Science:

Computational chemistry
Molecular dynamics
Drug discovery

Background:

Understanding ligand-receptor interactions is crucial for drug discovery.
Existing methods for analyzing ligand egress pathways have limitations.

Purpose of the Study:

To introduce a novel method, Minimal Steric Hindrance (MSH), for determining optimal ligand unbinding pathways.
To evaluate MSH's performance against existing methods in predicting binding affinities.

Main Methods:

Developed the MSH scoring function based on steric hindrance during ligand movement.
Utilized steered molecular dynamics (SMD) simulations.
Compared MSH with CAVER using three target-receptor systems.

Main Results:

MSH considers ligand geometry, unlike spherical models in CAVER.
MSH-derived rupture force (Fmax) and work (Wpull) showed higher correlation with experimental binding free energies than CAVER.
Nonequilibrium work (Wpull) proved a better indicator of binding affinity than Fmax.

Conclusions:

MSH is a reliable tool for identifying optimal ligand exit pathways from binding sites.
Combining MSH with SMD and using Wpull as a scoring function can effectively rank binding affinities.

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