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Flexible ligand docking using a genetic algorithm
C M Oshiro1, I D Kuntz, J S Dixon
1Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
Journal of Computer-Aided Molecular Design
|April 1, 1995
Summary
Two computational methods using Genetic Algorithm (GA) and DOCK programs explore enzyme-ligand interactions. These techniques accurately predict ligand conformations and orientations, offering potential for large-scale compound screening.
Area of Science:
- Computational chemistry
- Structural biology
- Drug discovery
Background:
- Understanding enzyme-ligand interactions is crucial for drug design.
- Exploring the conformational flexibility of ligands is computationally challenging.
Purpose of the Study:
- To develop and validate computational methods for exploring ligand binding within enzymes.
- To assess the potential of these methods for large-scale compound screening.
Main Methods:
- Utilized Genetic Algorithm (GA) for generating flexible ligand conformations.
- Employed DOCK algorithms to characterize enzyme receptor sites.
- Applied methods to dihydrofolate reductase, thymidylate synthase, and HIV protease complexes.
Main Results:
- Achieved conformations and orientations similar to crystallographically determined structures.
- Identified alternative low-energy binding poses.
- Demonstrated the feasibility of simultaneous evaluation of multiple ligands.
Conclusions:
- The developed GA-based methods effectively explore enzyme-ligand conformational and orientational space.
- These computational techniques show promise for efficient virtual screening of compound databases.