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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Rigorous Free Energy Calculations in Structure-Based Drug Design
Julien Michel1,2, Nicolas Foloppe3, Jonathan W Essex4
1Institute of Structural and Molecular Biology, The University of Edinburgh, Edinburgh, EH9 3JR, UK. mail@julienmichel.net.
Molecular Informatics
|July 28, 2016
Summary
Accurate prediction of binding affinity is crucial for drug design. Molecular simulations, such as free energy calculations, offer a more reliable approach than current scoring functions for identifying potent drug candidates.
Area of Science:
- Computational chemistry
- Molecular modeling
- Drug discovery
Background:
- Structure-based drug design relies on accurate prediction of binding affinity.
- Current docking scoring functions lack the precision for reliable virtual screening.
- Molecular simulations of protein-ligand complexes show promise for enhanced accuracy.
Purpose of the Study:
- To provide a comprehensive overview of binding free energy calculations.
- To detail the execution and analysis of free energy perturbation and thermodynamic integration methods.
- To discuss applications and limitations of these methods in drug design.
Main Methods:
- Free energy perturbation (FEP)
- Thermodynamic integration (TI)
- Molecular dynamics simulations of protein-ligand complexes
Main Results:
- Detailed technical aspects of FEP and TI methods are explained.
- Applications in structure-based drug design are illustrated.
- Current limitations and ongoing developments are highlighted.
Conclusions:
- Free energy calculations offer a more accurate alternative to docking scoring functions.
- Advancements in computing power make these methods increasingly practical.
- Ongoing developments aim to improve the scope, reliability, and usability of free energy calculations for molecular design.
Keywords:
Binding affinityDrug designFree energy perturbationMolecular recognitionThermodynamic integrationMore Related Videos
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