ArticleScientific reports2018
Predicting Binding Free Energies of PDE2 Inhibitors. The Difficulties of Protein Conformation.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Broad-spectrum coronavirus inhibitors discovered by modeling viral fusion dynamics.Frontiers in molecular biosciences · 2025Article
- Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system.Journal of computational chemistry · 2024Article
- Rapid, Accurate, Ranking of Protein-Ligand Binding Affinities with VM2, the Second-Generation Mining Minima Method.Journal of chemical theory and computation · 2024Article
- FEP Augmentation as a Means to Solve Data Paucity Problems for Machine Learning in Chemical Biology.Journal of chemical information and modeling · 2024Article
- Machine Learning Methods as a Cost-Effective Alternative to Physics-Based Binding Free Energy Calculations.Molecules (Basel, Switzerland) · 2024Article
- Chemical Space Exploration with Active Learning and Alchemical Free Energies.Journal of chemical theory and computation · 2022Article
- Exploring the Activity Profile of TbrPDEB1 and hPDE4 Inhibitors Using Free Energy Perturbation.ACS medicinal chemistry letters · 2022Article
- Ensemble Simulations and Experimental Free Energy Distributions: Evaluation and Characterization of Isoxazole Amides as SMYD3 Inhibitors.Journal of chemical information and modeling · 2022Article
- Large Scale Study of Ligand-Protein Relative Binding Free Energy Calculations: Actionable Predictions from Statistically Robust Protocols.Journal of chemical theory and computation · 2022Article
- Best practices for constructing, preparing, and evaluating protein-ligand binding affinity benchmarks [Article v0.1].Living journal of computational molecular science · 2022Article
- Alchemical absolute protein-ligand binding free energies for drug design.Chemical science · 2021Article
- Identification of SARS-CoV-2 Main Protease Inhibitors Using Structure Based Virtual Screening and Molecular Dynamics Simulation of DrugBank Database.ChemistrySelect · 2021Article
- Machine learning-accelerated quantum mechanics-based atomistic simulations for industrial applications.Journal of computer-aided molecular design · 2021Article
- In Vitro and In Silico Analysis of Ascorbic Acid Towards Lanosterol 14-α-Demethylase Enzyme of Fluconazole-Resistant Candida albicans.Current microbiology · 2021Article
- 1Biomolecules · 2020Article
- Best Practices for Alchemical Free Energy Calculations [Article v1.0].Living journal of computational molecular science · 2020Article
- Accuracy and Precision of Alchemical Relative Free Energy Predictions with and without Replica-Exchange.Advanced theory and simulations · 2020Article
- Free-energy landscape of molecular interactions between endothelin 1 and human endothelin type B receptor: fly-casting mechanism.Protein engineering, design & selection : PEDS · 2019Article
- DeltaDelta neural networks for lead optimization of small molecule potency.Chemical science · 2019Article
- Large scale relative protein ligand binding affinities using non-equilibrium alchemy.Chemical science · 2019Article
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A congeneric series of 21 phosphodiesterase 2 (PDE2) inhibitors are reported. Crystal structures show how the molecules can occupy a 'top-pocket' of the active site. Molecules with small substituents do not enter the pocket, a critical leucine (Leu770) is closed and water molecules are present. Large substituents enter the pocket, opening the Leu770 conformation and displacing the waters. We also report an X-ray structure revealing a new conformation of the PDE2 active site domain. The relative binding affinities of these compounds were studied with free energy perturbation (FEP) methods and it represents an attractive real-world test case. In general, the calculations could predict the energy of small-to-small, or large-to-large molecule perturbations. However, accurately capturing the transition from small-to-large proved challenging. Only when using alternative protein conformations did results improve. The new X-ray structure, along with a modelled dimer, conferred stability to the catalytic domain during the FEP molecular dynamics (MD) simulations, increasing the convergence and thereby improving the prediction of ΔΔG of binding for some small-to-large transitions. In summary, we found the most significant improvement in results when using different protein structures, and this data set is useful for future free energy validation studies.
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