ArticleThe Journal of biological chemistry2015
Contributions of ionic interactions and protein dynamics to cytochrome P450 2D6 (CYP2D6) substrate and inhibitor binding.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 104 citations in OpenAlex.
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- Water Migration through Enzyme Tunnels Is Sensitive to the Choice of Explicit Water Model.Journal of chemical information and modeling · 2025Article
- Investigation ofComputational and structural biotechnology journal · 2024Review
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- Elucidating the Mechanism of Metabolism of Cannabichromene by Human Cytochrome P450s.Journal of natural products · 2024Article
- Computational Binding Study Hints at Ecdysone 20-Mono-Oxygenase as the Hitherto Unknown Target for Ring C-Seco Limonoid-Type Insecticides.Molecules (Basel, Switzerland) · 2024Article
- In Silico and Chromatographic Methods for Analysis of Biotransformation of Prospective Neuroprotective Pyrrole-Based Hydrazone in Isolated Rat Hepatocytes.Molecules (Basel, Switzerland) · 2024Article
- ChannelsDB 2.0: a comprehensive database of protein tunnels and pores in AlphaFold era.Nucleic acids research · 2024Article
- A Robust Machine Learning Framework Built Upon Molecular Representations Predicts CYP450 Inhibition: Toward Precision in Drug Repurposing.Omics : a journal of integrative biology · 2023Article
- Nanodisc-embedded cytochrome P450 P3A4 binds diverse ligands by distributing conformational dynamics to its flexible elements.Journal of inorganic biochemistry · 2023Article
- Cytochrome P450 Surface Domains Prevent the β-Carotene Monohydroxylase CYP97H1 ofBiomolecules · 2023Article
- Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles.International journal of molecular sciences · 2023Review
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- Assessment of the Effects of Triticonazole on Soil and Human Health.Molecules (Basel, Switzerland) · 2022Article
- In Silico Design and SAR Study of Dibenzyl Trisulfide Analogues for Improved CYP1A1 Inhibition.ChemistryOpen · 2022Article
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- Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9.PLoS computational biology · 2022Article
- Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms.Biochemistry · 2021Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
P450 2D6 contributes significantly to the metabolism of >15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were obtained using different crystallization conditions. The protonated piperidine moiety of thioridazine forms a charge-stabilized hydrogen bond with Asp-301 in the active sites of both complexes. The more open conformation exhibits a second molecule of thioridazine bound in an expanded substrate access channel antechamber with its piperidine moiety forming a charge-stabilized hydrogen bond with Glu-222. Incubation of the crystalline open thioridazine complex with alternative ligands, prinomastat, quinidine, quinine, or ajmalicine, displaced both thioridazines. Quinine and ajmalicine formed charge-stabilized hydrogen bonds with Glu-216, whereas the protonated nitrogen of quinidine is equidistant from Asp-301 and Glu-216 with protonated nitrogen H-bonded to a water molecule in the access channel. Prinomastat is not ionized. Adaptations of active site side-chain rotamers and polypeptide conformations were evident between the complexes, with the binding of ajmalicine eliciting a closure of the open structure reflecting in part the inward movement of Glu-216 to form a hydrogen bond with ajmalicine as well as sparse lattice restraints that would hinder adaptations. These results indicate that P450 2D6 exhibits sufficient elasticity within the crystal lattice to allow the passage of compounds between the active site and bulk solvent and to adopt a more closed form that adapts for binding alternative ligands with different degrees of closure. These crystals provide a means to characterize substrate and inhibitor binding to the enzyme after replacement of thioridazine with alternative compounds.
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