ArticleThe journal of physical chemistry. B2025
IMERGE-FEP: Improving Relative Free Energy Calculation Convergence with Chemical Intermediates.
Article in The journal of physical chemistry. B, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- PairMap2: A Web Application for Intermediate-Molecule Insertion in Relative Binding Free Energy Calculations.Molecular informatics · 2026Article
- Emerging Insights into the Distinct Pharmacological Mechanisms of Buprenorphine.Journal of chemical information and modeling · 2026Article
- Large-Scale Collaborative Assessment of Binding Free Energy Calculations for Drug Discovery Using OpenFE.Journal of chemical information and modeling · 2026Article
Corrections and comments
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Authors and funding
10 authors.
Funding
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Abstract
Alchemical free energy calculations are becoming an increasingly prevalent tool in drug discovery efforts. Over the past decade, significant progress has been made in automating various aspects of this technique. However, one aspect hampering wider application is the construction of perturbation networks to connect ligands of interest. More specifically, ligand pairs with large dissimilarities should be avoided since they can lower convergence and decrease accuracy. Here, we propose a technique for automatic generation of intermediate molecules to break up problematic edges─calculations connecting two different ligands or molecules─into smaller perturbations. To this end, a modular tool was developed that generates intermediates for a molecule pair by enumerating R-group combinations called IMERGE-FEP (Intermediate MolEculaR GEnerator for Free Energy Perturbation). Intermediate enumeration of multiple, representative congeneric series showed that intermediates increase similarity regarding shared substructures, geometry, and LOMAP scores. Taken together, this tool eases integration of intermediate steps into free energy calculation protocols.
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Registered trials
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