ArticleProceedings of the National Academy of Sciences of the United States of America2023
Structural and thermodynamic framework for PIEZO1 modulation by small molecules.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Yoda1-Functionalized Nanozymes Coordinate Piezo1 Activation and Mitochondrial Protection to Reprogram the Diabetic Osteoimmune Micromilieu and Promote Vascularized Bone Repair.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Automated pharmacophore hypothesis generator for SILCS-Pharm: ph4gen.Journal of computer-aided molecular design · 2026Article
- Docking-score landscapes shape active-learning performance across Vina, Glide, and SILCS.Journal of computer-aided molecular design · 2026Article
- Piezo1 channel: structure, mechanogating mechanism, functions, diseases and therapeutic strategy.Molecular biomedicine · 2026Review
- A two-step clockwork mechanism opens a proteo-lipidic pore in PIEZO2.Nature chemical biology · 2026Article
- DICL: a manually curated database of ion channels and ligands as a useful platform for drug discovery targeting ion channels.Journal of cheminformatics · 2026Article
- Yoda molecules agonize PIEZO2.bioRxiv : the preprint server for biology · 2026Article
- Mechanical regulation of metabolism, epigenetics, and their interplay.npj biomedical innovations · 2026Review
- The role of Piezo1 in immune cells and pregnancy.Frontiers in immunology · 2026Review
- Piezo1-mediated mechanotransduction and metabolic regulation in bone health: molecular mechanisms and implications for bone disorders.Frontiers in cell and developmental biology · 2026Review
- Targeting Piezo1/2 ion channels for modulation of the lymphatic system: mechanisms, applications, and therapeutic prospects.Burns & trauma · 2026Review
- Ligand-Binding Free Energy Simulations of Membrane Proteins.Advances in experimental medicine and biology · 2026Review
- Advances in Fragment-based Drug Design: Lessons and Innovations from the Post-COVID Drug Discovery Landscape.Mini reviews in medicinal chemistry · 2026Review
- 3D-MINFLUX nanoscopy reveals distinct allosteric mechanisms for activation and modulation of PIEZO1 by Yoda1.Nature communications · 2025Article
- Cluster nanoarchitecture and structural diversity of PIEZO1 at rest and during activation in intact cells.Science advances · 2025Article
- The fetal hydrops-associated single-residue mutation L322P disrupts mechanical but not chemical activation of the PIEZO1 ion channel.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Pharmacology of PIEZO1 channels.British journal of pharmacology · 2024Review
- Mechanisms of mechanotransduction and physiological roles of PIEZO channels.Nature reviews. Molecular cell biology · 2024Review
- Piezo ion channels: long-sought-after mechanosensors mediating hypertension and hypertensive nephropathy.Hypertension research : official journal of the Japanese Society of Hypertension · 2024Review
- Ligand Binding Affinity Prediction for Membrane Proteins with Alchemical Free Energy Calculation Methods.Journal of chemical information and modeling · 2024Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Mechanosensitive PIEZO channels constitute potential pharmacological targets for multiple clinical conditions, spurring the search for potent chemical PIEZO modulators. Among them is Yoda1, a widely used synthetic small molecule PIEZO1 activator discovered through cell-based high-throughput screening. Yoda1 is thought to bind to PIEZO1's mechanosensory arm domain, sandwiched between two transmembrane regions near the channel pore. However, how the binding of Yoda1 to this region promotes channel activation remains elusive. Here, we first demonstrate that cross-linking PIEZO1 repeats A and B with disulfide bridges reduces the effects of Yoda1 in a redox-dependent manner, suggesting that Yoda1 acts by perturbing the contact between these repeats. Using molecular dynamics-based absolute binding free energy simulations, we next show that Yoda1 preferentially occupies a deeper, amphipathic binding site with higher affinity in PIEZO1 open state. Using Yoda1's binding poses in open and closed states, relative binding free energy simulations were conducted in the membrane environment, recapitulating structure-activity relationships of known Yoda1 analogs. Through virtual screening of an 8 million-compound library using computed fragment maps of the Yoda1 binding site, we subsequently identified two chemical scaffolds with agonist activity toward PIEZO1. This study supports a pharmacological model in which Yoda1 activates PIEZO1 by wedging repeats A and B, providing a structural and thermodynamic framework for the rational design of PIEZO1 modulators. Beyond PIEZO channels, the three orthogonal computational approaches employed here represent a promising path toward drug discovery in highly heterogeneous membrane protein systems.
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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.