ArticleThe Journal of chemical physics2016
A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4.
Article in The Journal of chemical physics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.Journal of biomolecular structure & dynamics · 2025Article
- Tryptophan-75 Is a Low-Energy Channel-Gating Residue that Facilitates Substrate Egress/Access in Cytochrome P450 2D6.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Molecular mechanisms of fentanyl mediated β-arrestin biased signaling.PLoS computational biology · 2020Article
- The finger loop of the SRA domain in the E3 ligase UHRF1 is a regulator of ubiquitin targeting and is required for the maintenance of DNA methylation.The Journal of biological chemistry · 2019Article
- Rolapitant Is a Reversible Inhibitor of CYP2D6.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
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- Modern drug design: the implication of using artificial neuronal networks and multiple molecular dynamic simulations.Journal of computer-aided molecular design · 2018Article
- Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations.ACS omega · 2017Article
- Attach-Pull-Release Calculations of Ligand Binding and Conformational Changes on the First BRD4 Bromodomain.Journal of chemical theory and computation · 2017Article
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5 authors.
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Abstract
In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a -3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class.
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