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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Multi-target dopamine D3 receptor modulators: Actionable knowledge for drug design from molecular dynamics and
Mariarosaria Ferraro1, Sergio Decherchi2, Alessio De Simone3
1Istituto di Chimica Del Riconoscimento Molecolare, Consiglio Nazionale Delle Ricerche (ICRM-CNR), Via Mario Bianco 9, 20131, Milan, Italy.
European Journal of Medicinal Chemistry
|January 16, 2020
Summary
Investigating ligand flexibility using molecular dynamics simulations helps explain changes in G-protein coupled receptor (GPCR) drug efficacy. This approach aids in rationally designing new therapeutics for receptors like the Dopamine D3 Receptor (D3DR).
Area of Science:
- Pharmacology
- Computational Chemistry
- Structural Biology
Background:
- Modifications to G-protein coupled receptors (GPCR) binders impact their pharmacological profiles.
- Understanding the structural basis for efficacy changes in GPCR modulators can be challenging.
Purpose of the Study:
- To rationalize efficacy changes in Dopamine D3 Receptor (D3DR) modulators using molecular dynamics (MD) simulations.
- To explore the role of ligand flexibility in GPCR-ligand interactions and receptor stability.
Main Methods:
- Clustering of MD simulations of the eticlopride-bound inactive D3DR state.
- Analysis of receptor-ligand complex dynamics and ligand flexibility.
- Rational drug design based on computational modeling and structural insights.
Main Results:
- Increased ligand flexibility was observed to progressively destabilize the inactive D3DR crystal structure.
- A rationally designed partial agonist, based on these insights, was successfully synthesized and validated.
- Computational predictions aligned with experimental results, confirming the model's validity.
Conclusions:
- Investigating ligand flexibility via extended MD simulations can elucidate GPCR modulator efficacy.
- This computational approach serves as a valuable in silico tool for drug design, complementing functional assays.
Keywords:
Dopamine D3 receptorDrug designGPCRMTDLMachine learningMolecular dynamicsMolecular recognitionMutil-targetPolypharmacologyMore Related Videos
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