ArticleJournal of chemical information and modeling2020
Discovery of Novel Small-Molecule Calcium Sensitizers for Cardiac Troponin C: A Combined Virtual and Experimental Screening Approach.
Article in Journal of chemical information and modeling, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 29 citations in OpenAlex.
- Biosensing Platforms for Cardiac Biomarker Detection.ACS omega · 2024Review
- Mouse Models of Cardiomyopathies Caused by Mutations in Troponin C.International journal of molecular sciences · 2023Review
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscles and Structure-Activity Relationship.Journal of chemical information and modeling · 2023Article
- Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations.Journal of chemical information and modeling · 2023Article
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship.bioRxiv : the preprint server for biology · 2023Article
- Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.Journal of chemical information and modeling · 2022Article
- Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.Journal of chemical information and modeling · 2022Article
- In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators.International journal of molecular sciences · 2022Article
- The interplay between cardiac dyads and mitochondria regulated the calcium handling in cardiomyocytes.Frontiers in physiology · 2022Review
- Applications of machine learning in computer-aided drug discovery.QRB discovery · 2022Review
- Molecular dynamics provides new insights into the mechanism of calcium signal transduction and interdomain interactions in cardiac troponin.FEBS open bio · 2021Article
- Gaussian accelerated molecular dynamics (GaMD): principles and applications.Wiley interdisciplinary reviews. Computational molecular scienceArticle
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Heart failure is a leading cause of death throughout the world and is triggered by a disruption of the cardiac contractile machinery. This machinery is regulated in a calcium-dependent manner by the protein complex troponin. Calcium binds to the N-terminal domain of cardiac troponin C (cNTnC) setting into motion the cascade of events leading to muscle contraction. Because of the severity and prevalence of heart failure, there is a strong need to develop small-molecule therapeutics designed to increase the calcium sensitivity of cardiac troponin in order to treat this devastating condition. Molecules that are able to stabilize an open configuration of cNTnC and additionally facilitate the binding of the cardiac troponin I (cTnI) switch peptide have the potential to enable increased calcium sensitization and strengthened cardiac function. Here, we employed a high throughput virtual screening methodology built upon the ability of computational docking to reproduce known experimental results and to accurately recognize cNTnC conformations conducive to small molecule binding using a receiver operator characteristic curve analysis. This approach combined with concurrent stopped-flow kinetic experimental verification led to the identification of a number of sensitizers, which slowed the calcium off-rate. An initial hit, compound
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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.