ArticleJournal of chemical information and modeling2013
Molecular simulations of aromatase reveal new insights into the mechanism of ligand binding.
Article in Journal of chemical information and modeling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Pharmacophoric Investigation of a Natural Product-like Class of Aromatase Inhibitors Using Molecular Modeling.ACS omega · 2026Article
- Molecular Targets of Minor Cannabinoids in Breast Cancer: In Silico and In Vitro Studies.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Influence of cholesterol on kinetic parameters for human aromatase (P450 19A1) in phospholipid nanodiscs.Journal of inorganic biochemistry · 2023Article
- A Theoretical Study of Organotin Binding in Aromatase.International journal of molecular sciences · 2023Article
- Article
- Polymorphism on human aromatase affects protein dynamics and substrate binding: spectroscopic evidence.Biology direct · 2021Article
- Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens.International journal of molecular sciences · 2020Review
- Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors.ACS medicinal chemistry letters · 2020Article
- The Effect of Force-Field Parameters on Cytochrome P450-Membrane Interactions: Structure and Dynamics.Scientific reports · 2020Article
- Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19.International journal of molecular sciences · 2019Article
- Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function.Biophysical journal · 2019Article
- Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer.Nature genetics · 2017Article
- Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.Journal of medicinal chemistry · 2016Review
- Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer.International journal of clinical and experimental pathology · 2015Article
- Anatomy of enzyme channels.BMC bioinformatics · 2014Article
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3 authors.
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Abstract
CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model of the lipid bilayer and the transmembrane helix are performed. The dynamics of aromatase and the role of titration of an important amino acid residue involved in aromatization of androgens are investigated via two 250-ns long simulations. One simulation treats the protonated form of the catalytic aspartate 309, which appears more consistent with crystallographic data for the active site, while the simulation of the deprotonated form shows some notable conformational shifts. Ensemble-based computational solvent mapping experiments indicate possible novel druggable binding sites that could be utilized by next-generation inhibitors. In addition, the effects of protonation on the ligand positioning and channel dynamics are investigated using geometrical models that estimate the opening width of critical channels. Significant differences in channel dynamics between the protonated and deprotonated trajectories are exhibited, suggesting that the mechanism for substrate and product entry and the aromatization process may be coupled to a "locking" mechanism and channel opening. Our results may be particularly relevant in the design of novel drugs, which may be useful therapeutic treatments of cancers such as those of the breast and prostate.
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