ArticleBiochimica et biophysica acta2016
Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design.
Article in Biochimica et biophysica acta, 2016. 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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15 citing papers in PubMed, 23 citations in OpenAlex.
- Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane-bound cytochrome P450 2B4.Protein science : a publication of the Protein Society · 2024Article
- Identification of Potent and Selective Inhibitors ofJournal of medicinal chemistry · 2024Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- 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
- The Effect of Force-Field Parameters on Cytochrome P450-Membrane Interactions: Structure and Dynamics.Scientific reports · 2020Article
- Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51.Frontiers in molecular biosciences · 2020Article
- Advances in preclinical approaches to Chagas disease drug discovery.Expert opinion on drug discovery · 2019Review
- Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19.International journal of molecular sciences · 2019Article
- Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance.Chemical reviews · 2019Article
- CYP51 as drug targets for fungi and protozoan parasites: past, present and future.Parasitology · 2018Review
- Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery.Antimicrobial agents and chemotherapy · 2018Article
- Sterol 14α-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis.Journal of medicinal chemistry · 2018Article
- Escape of a Small Molecule from Inside T4 Lysozyme by Multiple Pathways.Biophysical journal · 2018Article
- Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model.PLoS neglected tropical diseases · 2016Article
- Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design.Journal of lipid research · 2016Article
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundCytochrome P450 sterol 14α-demethylase (CYP51) is an essential enzyme for sterol biosynthesis and a target for anti-parasitic drug design. However, the design of parasite-specific drugs that inhibit parasitic CYP51 without severe side effects remains challenging. The active site of CYP51 is situated in the interior of the protein. Here, we characterize the potential ligand egress routes and mechanisms in Trypanosoma brucei and human CYP51 enzymes.
methodsWe performed Random Acceleration Molecular Dynamics simulations of the egress of four different ligands from the active site of models of soluble and membrane-bound T. brucei CYP51 and of soluble human CYP51.
resultsIn the simulations, tunnel 2f, which leads to the membrane, was found to be the predominant ligand egress tunnel for all the ligands studied. Tunnels S, 1 and W, which lead to the cytosol, were also used in T. brucei CYP51, whereas tunnel 1 was the only other tunnel used significantly in human CYP51. The common tunnels found previously in other CYPs were barely used. The ligand egress times were shorter for human than T. brucei CYP51, suggesting lower barriers to ligand passage. Two gating residues, F105 and M460, in T. brucei CYP51 that modulate the opening of tunnels 2f and S were identified.
conclusionsAlthough the main egress tunnel was the same, differences in the tunnel-lining residues, ligand passage and tunnel usage were found between T. brucei and human CYP51s. GENERAL SIGNIFICANCE: The results provide a basis for the design of selective anti-parasitic agents targeting the ligand tunnels.
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