ArticleJournal of medicinal chemistry2017
When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?
Article in Journal of medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Predicting Ligand Binding Modes by Scaffold-Guided Structure Refinement.Journal of medicinal chemistry · 2026Article
- Evaluating generalization in protein-ligand cofolding methods.Nature structural & molecular biology · 2026Article
- Can AI-Predicted Complexes Teach Machine Learning to Compute Drug Binding Affinity?Journal of chemical information and modeling · 2025Article
- Core Flipping in Lead Optimization: Rank Ordering Using λ-Dynamics.Journal of chemical information and modeling · 2025Article
- Template-Based Docking Using Automated Maximum Common Substructure Identification with EnzyDock: Mechanistic and Inhibitor Docking.Journal of chemical information and modeling · 2025Article
- Moldrug algorithm for an automated ligand binding site exploration by 3D aware molecular enumerations.Journal of cheminformatics · 2025Article
- Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization.Journal of medicinal chemistry · 2025Article
- Macromolecular crystallography from an industrial perspective - the impact of synchrotron radiation on structure-based drug discovery.Journal of synchrotron radiation · 2025Article
- Durlobactam in combination with β-lactams to combatAntimicrobial agents and chemotherapy · 2025Article
- Fragmenstein: predicting protein-ligand structures of compounds derived from known crystallographic fragment hits using a strict conserved-binding-based methodology.Journal of cheminformatics · 2025Article
- Investigation into the Potential Mechanism of Radix Paeoniae Rubra Against Ischemic Stroke Based on Network Pharmacology.Nutrients · 2024Article
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- SpaceGrow: efficient shape-based virtual screening of billion-sized combinatorial fragment spaces.Journal of computer-aided molecular design · 2024Article
- Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.ACS medicinal chemistry letters · 2024Article
- Conformation-dependent ligand hot spots in the spliceosomal RNA helicase BRR2.Acta crystallographica. Section D, Structural biology · 2023Article
- What Makes GPCRs from Different Families Bind to the Same Ligand?Biomolecules · 2022Article
- SAMPL7 protein-ligand challenge: A community-wide evaluation of computational methods against fragment screening and pose-prediction.Journal of computer-aided molecular design · 2022Article
- Leveraging nonstructural data to predict structures and affinities of protein-ligand complexes.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Deep generative design with 3D pharmacophoric constraints.Chemical science · 2021Article
- Discovery of SARS-CoV-2 MChemical science · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
2 authors.
Funding
Abstract
Traditional hit-to-lead optimization assumes that upon elaboration of chemical structure, the ligand retains its binding mode relative to the receptor. Here, we build a large-scale collection of related ligand pairs solved in complex with the same protein partner: we find that for 41 of 297 pairs (14%), the binding mode changes upon elaboration of the smaller ligand. While certain ligand physiochemical properties predispose changes in binding mode, particularly those properties that define fragments, simple structure-based modeling proves far more effective for identifying substitutions that alter the binding mode. Some ligand pairs change binding mode because the added substituent would irreconcilably conflict with the receptor in the original pose, whereas others change because the added substituent enables new, stronger interactions that are available only in a different pose. Scaffolds that can engage their target using alternate poses may enable productive structure-based optimization along multiple divergent pathways.
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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.