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Flexible docking using Tabu search and an empirical estimate of binding affinity
C A Baxter1, C W Murray, D E Clark
1Proteus Molecular Design Ltd., Macclesfield, Cheshire, United Kingdom.
Proteins
|November 26, 1998
Summary
This study introduces a new molecular docking method using Tabu search for flexible ligands and rigid receptors. The approach accurately predicts ligand binding affinities and geometries, showing promise for drug discovery.
Area of Science:
- Computational Chemistry
- Structural Biology
- Drug Discovery
Background:
- Molecular docking is crucial for predicting ligand-receptor interactions.
- Accurate prediction of binding affinity and geometry remains a challenge.
- Existing methods often struggle with flexible ligands.
Purpose of the Study:
- To implement and validate a novel molecular docking approach.
- To assess the accuracy of predicting ligand binding affinities.
- To evaluate the prediction of ligand-receptor binding geometries.
Main Methods:
- Utilized Tabu search methodology for molecular docking.
- Employed an empirical objective function with physically based terms.
- Docked flexible ligand molecules into rigid receptor structures.
- Minimized ligand molecules in vacuo before docking.
Main Results:
- The method achieved high accuracy in predicting binding modes (86% within 1.5 Å RMSD).
- Docking energies showed fair agreement with experimental free energies of binding.
- Successfully tested on 50 diverse ligand-receptor complexes.
Conclusions:
- The new docking approach effectively predicts ligand binding affinities and geometries.
- This method offers a reliable tool for structure-based drug design.
- The approach demonstrates significant potential for accelerating drug discovery efforts.