The effect of multiple simulation parameters on MM/PBSA performance for binding affinity prediction of CB1 cannabinoid receptor agonists and antagonists
| Autor: | Amelia Y. Y. Yong, Jason S. E. Loo, Yen Nee Yong |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Cannabinoid receptor
Thermodynamics Crystal structure Dielectric Molecular Dynamics Simulation 01 natural sciences Biochemistry Molecular dynamics symbols.namesake Receptor Cannabinoid CB1 Drug Discovery Molecule Poisson Distribution Cannabinoid Receptor Agonists Pharmacology 010405 organic chemistry Chemistry Organic Chemistry Potential method 0104 chemical sciences 010404 medicinal & biomolecular chemistry Boltzmann constant symbols Molecular Medicine Protein Binding |
| Zdroj: | Chemical Biology & Drug Design. 96:1244-1254 |
| ISSN: | 1747-0285 1747-0277 |
| DOI: | 10.1111/cbdd.13733 |
| Popis: | Both the inactive- and active-state CB1 receptor crystal structures have now been solved, allowing their application in various structure-based drug design methods. One potential method utilizing these crystal structures is the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method of predicting relative binding free energies. However, MM/PBSA performance is sensitive to various simulation parameters and often requires optimization for the system of interest. In this study, we evaluated the effects of various simulation parameters, namely simulation length, choice of dielectric constant, inclusion of explicit water molecules, and inclusion of entropy, on the ability of MM/PBSA to predict the experimental binding free energies of a set of known CB1 agonists and antagonists. MM/PBSA produced r values ranging from 0.410 to 0.688 for the CB1 agonists and 0.420 to 0.678 for the CB1 antagonists depending on the simulation parameters, which were modestly better than correlations obtained using docking scores. Using fewer replicates with a longer simulation length and a higher solute dielectric constant value had the largest positive effect on performance. Including explicit water molecules at the protein-ligand interface had a minor positive effect on performance at higher dielectric constant values, while the inclusion of entropy had a detrimental effect across most of the data set. |
| Databáze: | OpenAIRE |
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