4xry

Human Cytochrome P450 2D6 BACE1 Inhibitor 5 Complex

spinqualitylabelsall models 4xry, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4xry is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, SI5, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CP2D6_HUMAN Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants. Publication Abstract from PubMed In recent years, the first generation of beta-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogs with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins. Utilizing CYP2D6 and BACE1 Structure Complexes to Reduce Risk of Drug-Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors.,Brodney MA, Beck EM, Butler CR, Barreiro G, Johnson EF, Riddell D, Parris K, Nolan CE, Fan Y, Atchison K, Gonzales C, Robshaw A, Doran SD, Bundesmann MW, Buzon LM, Dutra JK, Henegar KE, LaChapelle EA, Hou X, Rogers BN, Pandit J, Lira R, Martinez-Alsina LA, Mikochik P, Murray JC, Ogilvie K, Price L, Sakya S, Yu A, Zhang Y, O'Neill BT J Med Chem. 2015 Mar 17. PMID:25781223 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome P450 3D structures

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