ArticleJournal of the American Chemical Society2017
Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed.
- Comparative Assessment of Free Energy Computational Methods for Revealing the Interactions Driving PARP1 Selective Inhibition.Journal of chemical information and modeling · 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
- An efficient computational chemistry approach to generating negative data for drug discovery pipeline validation.Frontiers in bioinformatics · 2026Article
- Evaluation of the ABCG2 Charge Model in Protein-Ligand Binding Free-Energy Calculations.Journal of chemical information and modeling · 2025Article
- Identification of novel dihydroorotate dehydrogenase (DHODH) inhibitors for cancer: computational drug repurposing strategy.BMC pharmacology & toxicology · 2025Article
- Machine Learning-Enhanced Calculation of Quantum-Classical Binding Free Energies.Journal of chemical theory and computation · 2025Article
- Quantification of the Impact of Structure Quality on Predicted Binding Free Energy Accuracy.Journal of chemical information and modeling · 2025Article
- Core Flipping in Lead Optimization: Rank Ordering Using λ-Dynamics.Journal of chemical information and modeling · 2025Article
- Article
- Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints.Journal of chemical theory and computation · 2025Article
- Equilibrium and Nonequilibrium Ensemble Methods for Accurate, Precise and Reproducible Absolute Binding Free Energy Calculations.Journal of chemical theory and computation · 2025Article
- Discovery of highly potent phosphodiesterase-1 inhibitors by a combined-structure free energy perturbation approach.Acta pharmaceutica Sinica. B · 2024Article
- Analysis of Glycan Recognition by Concanavalin A Using Absolute Binding Free Energy Calculations.Journal of chemical information and modeling · 2024Article
- Automated Adaptive Absolute Binding Free Energy Calculations.Journal of chemical theory and computation · 2024Article
- Structure-aware dual-target drug design through collaborative learning of pharmacophore combination and molecular simulation.Chemical science · 2024Article
- Computational Analysis of Heat Capacity Effects in Protein-Ligand Binding.Journal of chemical theory and computation · 2024Article
- Alchemical Enhanced Sampling with Optimized Phase Space Overlap.Journal of chemical theory and computation · 2024Article
- Tuning Potential Functions to Host-Guest Binding Data.Journal of chemical theory and computation · 2024Article
- Roles of Accelerated Molecular Dynamics Simulations in Predictions of Binding Kinetic Parameters.Mini reviews in medicinal chemistry · 2024Review
- Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes.Journal of enzyme inhibition and medicinal chemistry · 2023Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors.
Funding
Abstract
Binding selectivity is a requirement for the development of a safe drug, and it is a critical property for chemical probes used in preclinical target validation. Engineering selectivity adds considerable complexity to the rational design of new drugs, as it involves the optimization of multiple binding affinities. Computationally, the prediction of binding selectivity is a challenge, and generally applicable methodologies are still not available to the computational and medicinal chemistry communities. Absolute binding free energy calculations based on alchemical pathways provide a rigorous framework for affinity predictions and could thus offer a general approach to the problem. We evaluated the performance of free energy calculations based on molecular dynamics for the prediction of selectivity by estimating the affinity profile of three bromodomain inhibitors across multiple bromodomain families, and by comparing the results to isothermal titration calorimetry data. Two case studies were considered. In the first one, the affinities of two similar ligands for seven bromodomains were calculated and returned excellent agreement with experiment (mean unsigned error of 0.81 kcal/mol and Pearson correlation of 0.75). In this test case, we also show how the preferred binding orientation of a ligand for different proteins can be estimated via free energy calculations. In the second case, the affinities of a broad-spectrum inhibitor for 22 bromodomains were calculated and returned a more modest accuracy (mean unsigned error of 1.76 kcal/mol and Pearson correlation of 0.48); however, the reparametrization of a sulfonamide moiety improved the agreement with experiment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.