ArticleProceedings of the National Academy of Sciences of the United States of America2024
Global hinge sites of proteins as target sites for drug binding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed.
- DruGUI 2.0: mapping protein druggability with probe-based molecular dynamics.Bioinformatics (Oxford, England) · 2026Article
- Minimal Computational Framework for Systematic Identification of Antimicrobial Targets.bioRxiv : the preprint server for biology · 2026Article
- Allosteric drugs in biomolecular condensates: ways forward.Drug discovery today · 2026Review
- Conformation Driven Enhancement of Neurolysin Activity in Presence of a Small Molecule Activator.bioRxiv : the preprint server for biology · 2026Article
- Allosteric Autoregulation of Ferroptosis Suppressor Protein 1 Activity by its N-myristoylated Tail.Journal of molecular biology · 2025Article
- The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives.Journal of molecular biology · 2025Review
- Decoding Mechanisms of PTEN Missense Mutations in Cancer and Autism Spectrum Disorder using Interpretable Machine Learning Approaches.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Hinge sites of proteins play a key role in mediating conformational mechanics. Among them, those involved in the most collective modes of motion, also called global hinges, are of particular interest, as they support cooperative rearrangements that are often functional. Yet, the utility of targeting global hinges for modulating function remains to be established. We present here a systematic study of a series of proteins resolved in drug-bound forms to examine the probabilistic occurrence of spatial overlaps between hinge sites and drug-binding pockets. Our analysis reveals a high propensity of drug binding to hinge sites compared to random. Notably, one-third of currently approved drugs are colocalized with hinge sites. These mechanosensitive sites are predictable by simple models such as the Gaussian Network Model. Their targeting thus emerges as a viable strategy for developing a new class of drugs that would exploit and modulate the target proteins' intrinsic dynamics, and potentially alleviate drug-resistance when used in combination with orthosteric or allosteric drugs.
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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 Socratic graph.