ArticleRSC medicinal chemistry2020
A structure-kinetic relationship study using matched molecular pair analysis.
Article in RSC medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
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Who cites it
11 citing papers in PubMed.
- Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.bioRxiv : the preprint server for biology · 2026Article
- Altered residence time as a cause of drug resistance.Current opinion in structural biology · 2026Review
- Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects.Journal of the American Chemical Society · 2025Article
- Applying Computational Protein Design to Engineer Affibodies for Affinity-controlled Delivery of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor.Biomacromolecules · 2025Article
- ModBind, a Rapid Simulation-Based Predictor of Ligand Binding and Off-Rates.Journal of chemical information and modeling · 2025Article
- Catalytic activities of wild-type C. elegans DAF-2 kinase and dauer-associated mutants.The FEBS journal · 2024Article
- Article
- Machine learning methods for developments of binding kinetic models in predicting protein-ligand dissociation rate constants.Smart molecules : open access · 2023Article
- Slow Dissociation from the PARP1-HPF1 Complex Drives Inhibitor Potency.Biochemistry · 2023Article
- Predicting Biomolecular Binding Kinetics: A Review.Journal of chemical theory and computation · 2023Review
- Predicting Residence Time of GPCR Ligands with Machine Learning.Methods in molecular biology (Clifton, N.J.) · 2022Article
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The lifetime of a binary drug-target complex is increasingly acknowledged as an important parameter for drug efficacy and safety. With a better understanding of binding kinetics and better knowledge about kinetic parameter optimization, intentionally induced prolongation of the drug-target residence time through structural changes of the ligand could become feasible. In this study we assembled datasets from 21 publications and the K4DD (Kinetic for Drug Discovery) database to conduct large scale data analysis. This resulted in 3812 small molecules annotated to 78 different targets from five protein classes (GPCRs: 273, kinases: 3238, other enzymes: 240, HSPs: 160, ion channels: 45). Performing matched molecular pair (MMP) analysis to further investigate the structure-kinetic relationship (SKR) in this data collection allowed us to identify a fundamental contribution of a ligand's polarity to its association rate, and in selected cases, also to its dissociation rate. However, we furthermore observed that the destabilization of the transition state introduced by increased polarity is often accompanied by simultaneous destabilization of the ground state resulting in an unaffected or even worsened residence time. Supported by a set of case studies, we provide concepts on how to alter ligands in ways to trigger on-rates, off-rates, or both.
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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.