ArticleChemical science2021
Alchemical absolute protein-ligand binding free energies for drug design.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed.
- Computational identification of potential inhibitors for chikungunya virus nsP2pro.Royal Society open science · 2026Article
- Molecular Dynamics Workflows to Compute Large-Scale Sets of Absolute Binding Free Energies Aiding Drug Candidate and Binding Pose Selection.Journal of chemical theory and computation · 2026Article
- The Last Mile Problem: A Critical Assessment of Physics-Based and AI Tools for Small Molecule Binding Prediction in Virtual Screening.Journal of chemical information and modeling · 2026Article
- Toward Reconciling the Standard Binding Free Energy of Lenacapavir to HIV-1 Capsid with Experiment: Thermodynamic Effects of Solvent Buffer and Ligand Reorganization.The journal of physical chemistry. B · 2026Article
- BindFlow: A Free, User-Friendly Pipeline for Absolute Binding Free Energy Calculations Using Free Energy Perturbation or MM(PB/GB)SA.Journal of chemical theory and computation · 2026Article
- Prediction of Protein-Ligand Binding Affinities Using Atomic Surface Site Interaction Points.Journal of chemical information and modeling · 2026Article
- Evaluation of the ABCG2 Charge Model in Protein-Ligand Binding Free-Energy Calculations.Journal of chemical information and modeling · 2025Article
- Assessment of the Binding Patterns for Endocrine Disrupting Chemicals in Complex with Estrogen and Androgen Receptors by Leveraging the Asclepios Enalos KNIME Nodes.Journal of chemical information and modeling · 2025Article
- Integrating Machine Learning into Free Energy Perturbation Workflows.Journal of chemical information and modeling · 2025Review
- Molecular dynamics simulations of proteins: an in-depth review of computational strategies, structural insights, and their role in medicinal chemistry and drug development.Biological cybernetics · 2025Review
- Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters.Journal of chemical theory and computation · 2025Article
- Spatio-temporal learning from molecular dynamics simulations for protein-ligand binding affinity prediction.Bioinformatics (Oxford, England) · 2025Article
- Quantification of the Impact of Structure Quality on Predicted Binding Free Energy Accuracy.Journal of chemical information and modeling · 2025Article
- Automated On-the-Fly Optimization of Resource Allocation for Efficient Free Energy Simulations.Journal of chemical information and modeling · 2025Article
- Estimation of Absolute Binding Free Energies for Drugs That Bind Multiple Proteins.Journal of chemical information and modeling · 2025Article
- Equilibrium and Nonequilibrium Ensemble Methods for Accurate, Precise and Reproducible Absolute Binding Free Energy Calculations.Journal of chemical theory and computation · 2025Article
- Structure and dynamics in drug discovery.npj drug discovery · 2024Review
- Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system.Journal of computational chemistry · 2024Article
- Replica Exchange of Expanded Ensembles: A Generalized Ensemble Approach with Enhanced Flexibility and Parallelizability.Journal of chemical theory and computation · 2024Article
- Current State of Open Source Force Fields in Protein-Ligand Binding Affinity Predictions.Journal of chemical information and modeling · 2024Article
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based absolute binding free energy estimates for 128 pharmaceutically relevant targets. We use a novel rigorous method to generate protein-ligand ensembles for the ligand in its decoupled state. Not only do the calculations deliver accurate protein-ligand binding affinity estimates, but they also provide detailed physical insight into the structural determinants of binding. We identify subtle rotamer rearrangements between apo and holo states of a protein that are crucial for binding. When compared to relative binding free energy calculations, obtaining absolute binding free energies is considerably more challenging in large part due to the need to explicitly account for the protein in its apo state. In this work we present several approaches to obtain apo state ensembles for accurate absolute Δ
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