5TFU
Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex
Summary for 5TFU
| Entry DOI | 10.2210/pdb5tfu/pdb |
| Related | 5TFT |
| Descriptor | Cytochrome P450 2D6, PROTOPORPHYRIN IX CONTAINING FE, ZINC ION, ... (5 entities in total) |
| Functional Keywords | cyp2d6, p450 2d6, cytochrome p450, monooxygenase, bace1, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 219288.93 |
| Authors | Hsu, M.H.,Johnson, E.F. (deposition date: 2016-09-26, release date: 2017-01-11, Last modification date: 2023-10-04) |
| Primary citation | Butler, C.R.,Ogilvie, K.,Martinez-Alsina, L.,Barreiro, G.,Beck, E.M.,Nolan, C.E.,Atchison, K.,Benvenuti, E.,Buzon, L.,Doran, S.,Gonzales, C.,Helal, C.J.,Hou, X.,Hsu, M.H.,Johnson, E.F.,Lapham, K.,Lanyon, L.,Parris, K.,O'Neill, B.T.,Riddell, D.,Robshaw, A.,Vajdos, F.,Brodney, M.A. Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality. J. Med. Chem., 60:386-402, 2017 Cited by PubMed Abstract: A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor. PubMed: 27997172DOI: 10.1021/acs.jmedchem.6b01451 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.75 Å) |
Structure validation
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