ArticleScientific reports2019
An Improved Free Energy Perturbation FEP+ Sampling Protocol for Flexible Ligand-Binding Domains.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- A critical appraisal of structure-based virtual screening, binding free energy methods, and AI-driven molecular design across the evolving computational landscape of drug discovery.Journal of computer-aided molecular design · 2026Review
- Large-Scale Collaborative Assessment of Binding Free Energy Calculations for Drug Discovery Using OpenFE.Journal of chemical information and modeling · 2026Article
- Structure-based cheminformatics and molecular dynamics profiling of potential SIRT6 inhibitors.Molecular diversity · 2026Article
- Bridging Scales: Coarse-Grained Protein Models in Computational Biology.Advances in experimental medicine and biology · 2026Review
- Exploring Novel Inhibitory Compounds Against Phosphatase Gamma 2: A Therapeutic Target for Male Contraceptives.Current issues in molecular biology · 2025Article
- Discovery of Reversible, Noncovalent Bruton's Tyrosine Kinase Inhibitors Targeting BTK C481S Mutation.ACS medicinal chemistry letters · 2025Article
- Article
- Interformer: an interaction-aware model for protein-ligand docking and affinity prediction.Nature communications · 2024Article
- A Method for Treating Significant Conformational Changes in Alchemical Free Energy Simulations of Protein-Ligand Binding.Journal of chemical theory and computation · 2024Article
- Sample efficient reinforcement learning with active learning for molecular design.Chemical science · 2024Article
- Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases.Journal of chemical information and modeling · 2023Article
- Assessing the performance of docking, FEP, and MM/GBSA methods on a series of KLK6 inhibitors.Journal of computer-aided molecular design · 2023Article
- Binding and Dynamics Demonstrate the Destabilization of Ligand Binding for the S688Y Mutation in the NMDA Receptor GluN1 Subunit.Molecules (Basel, Switzerland) · 2023Article
- Past, Present, and Future Perspectives on Computer-Aided Drug Design Methodologies.Molecules (Basel, Switzerland) · 2023Review
- Automated relative binding free energy calculations from SMILES to ΔΔG.Communications chemistry · 2023Article
- Accelerated Enveloping Distribution Sampling (AEDS) Allows for Efficient Sampling of Orthogonal Degrees of Freedom.Journal of chemical information and modeling · 2023Article
- Assessing a computational pipeline to identify binding motifs to theFrontiers in chemistry · 2023Article
- Pathfinder-Driven Chemical Space Exploration and Multiparameter Optimization in Tandem with Glide/IFD and QSAR-Based Active Learning Approach to Prioritize Design Ideas for FEP+ Calculations of SARS-CoV-2 PLMolecules (Basel, Switzerland) · 2022Article
- Exploring the Activity Profile of TbrPDEB1 and hPDE4 Inhibitors Using Free Energy Perturbation.ACS medicinal chemistry letters · 2022Article
- A highly accurate metadynamics-based Dissociation Free Energy method to calculate protein-protein and protein-ligand binding potencies.Scientific reports · 2022Article
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Authors and funding
2 authors.
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Abstract
Recent improvements to the free energy perturbation (FEP) calculations, especially FEP+ , established their utility for pharmaceutical lead optimization. Herein, we propose a modified version of the FEP/REST (i.e., replica exchange with solute tempering) sampling protocol, based on detail studies on several targets by probing a large number of perturbations with different sampling schemes. Improved FEP+ binding affinity predictions for regular flexible-loop motions and considerable structural changes can be obtained by extending the prior to REST (pre-REST) sampling time from 0.24 ns/λ to 5 ns/λ and 2 × 10 ns/λ, respectively. With this new protocol, much more precise ∆∆G values of the individual perturbations, including the sign of the transformations and decreased error were obtained. We extended the REST simulations from 5 ns to 8 ns to achieve reasonable free energy convergence. Implementing REST to the entire ligand as opposed to solely the perturbed region, and also some important flexible protein residues (pREST region) in the ligand binding domain (LBD) has considerably improved the FEP+ results in most of the studied cases. Preliminary molecular dynamics (MD) runs were useful for establishing the correct binding mode of the compounds and thus precise alignment for FEP+ . Our improved protocol may further increase the FEP+ accuracy.
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