ArticleThe Journal of chemical physics2012
Perspective: Alchemical free energy calculations for drug discovery.
Article in The Journal of chemical physics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers.
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Who cites it
112 citing papers in PubMed.
- Benchmarking Docking Protocols on Predicting Alternative Binding Modes.Journal of chemical information and modeling · 2026Article
- FLOWR.ROOT - A flow matching-based foundation model for joint multi-purpose structure-aware 3D ligand generation and affinity prediction.Nature communications · 2026Article
- An Automated Workflow for Diagnosing Sampling Issues Caused by Slow Torsional Motions in Molecular Simulations.Journal of chemical information and modeling · 2026Article
- A Risk-Tiered Validation Framework for Artificial Intelligence in Drug Discovery: From Reproducibility to Clinical Translation.International journal of molecular sciences · 2026Review
- Efficient Binding Affinity Estimation for Fragment-Based Compounds Using a Separated Topologies Approach.Journal of chemical information and modeling · 2026Article
- The Open Molecular Software Foundation (OMSF) and the Growing Role of Open Source Software in Molecular Modeling.Journal of chemical information and modeling · 2026Review
- Ligand-Binding Free Energy Simulations of Membrane Proteins.Advances in experimental medicine and biology · 2026Review
- SAMTI: Sampling Adaptive Thermodynamic Integration for Alchemical Free Energy Calculations.The journal of physical chemistry. B · 2025Article
- MnM-W-MMGBSA: A Computational Strategy to Improve Relative Binding Free Energies of Protein-Protein Interaction Systems.The journal of physical chemistry. B · 2025Article
- Free Energy Perturbation Simulations Measure the Change in Binding Affinity of the Aβ25-35 Peptide to the Zwitterionic Bilayer Caused by Oxidation.Journal of chemical information and modeling · 2025Article
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- Core Flipping in Lead Optimization: Rank Ordering Using λ-Dynamics.Journal of chemical information and modeling · 2025Article
- Multiple Molecule λ-Dynamics: Probing Drug Resistance with Concurrent Protein and Ligand Perturbations.The journal of physical chemistry letters · 2025Article
- Applying Absolute Free Energy Perturbation Molecular Dynamics to Diffusively Binding Ligands.Journal of chemical theory and computation · 2025Article
- PairMap: An Intermediate Insertion Approach for Improving the Accuracy of Relative Free Energy Perturbation Calculations for Distant Compound Transformations.Journal of chemical information and modeling · 2025Article
- Cortisol regulates neonatal lung development via Smoothened.Respiratory research · 2025Article
- Multiple Topology Replica Exchange of Expanded Ensembles for Multidimensional Alchemical Calculations.Journal of chemical theory and computation · 2025Article
- Kinetics-Based State Definitions for Discrete Binding Conformations of T4 L99A in MD via Markov State Modeling.Journal of chemical information and modeling · 2024Article
- Superimposing Ligands with a Ligand Overlay as an Alternate Topology Model for λ-Dynamics-Based Calculations.The journal of physical chemistry. B · 2024Article
52 more citing papers are in PubMed but not listed here.
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2 authors.
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Abstract
Computational techniques see widespread use in pharmaceutical drug discovery, but typically prove unreliable in predicting trends in protein-ligand binding. Alchemical free energy calculations seek to change that by providing rigorous binding free energies from molecular simulations. Given adequate sampling and an accurate enough force field, these techniques yield accurate free energy estimates. Recent innovations in alchemical techniques have sparked a resurgence of interest in these calculations. Still, many obstacles stand in the way of their routine application in a drug discovery context, including the one we focus on here, sampling. Sampling of binding modes poses a particular challenge as binding modes are often separated by large energy barriers, leading to slow transitions. Binding modes are difficult to predict, and in some cases multiple binding modes may contribute to binding. In view of these hurdles, we present a framework for dealing carefully with uncertainty in binding mode or conformation in the context of free energy calculations. With careful sampling, free energy techniques show considerable promise for aiding drug discovery.
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