PDBsum entry 4xrz

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4xrz

Contents

Protein chains

457 a.a.

Ligands

HEM-SI6 ×4

GOL ×4

Metals

_NA ×4

_ZN ×12

Waters ×343

PDB id:

4xrz

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Human cytochrome p450 2d6 bace1 inhibitor 6 complex

Structure:

Cytochrome p450 2d6. Chain: a, b, c, d. Fragment: unp residues 34-497. Synonym: cypiid6,cytochrome p450-db1,debrisoquine 4-hydroxylase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp2d6, cyp2dl1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.40Å R-factor: 0.219 R-free: 0.254

Authors:

E.F.Johnson,Y.Fan

Key ref:

M.A.Brodney et al. (2015). Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors. J Med Chem, 58, 3223-3252. PubMed id: 25781223 DOI: 10.1021/acs.jmedchem.5b00191

Date:

21-Jan-15 Release date: 20-May-15

Protein chains

P10635  (CP2D6_HUMAN) -  Cytochrome P450 2D6 from Homo sapiens

Seq: 497 a.a.

Struc: 457 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.14.14.- - ?????

DOI no: 10.1021/acs.jmedchem.5b00191

J Med Chem 58:3223-3252 (2015)

PubMed id: 25781223

Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.

M.A.Brodney, E.M.Beck, C.R.Butler, G.Barreiro, E.F.Johnson, D.Riddell, K.Parris, C.E.Nolan, Y.Fan, K.Atchison, C.Gonzales, A.E.Robshaw, S.D.Doran, M.W.Bundesmann, L.Buzon, J.Dutra, K.Henegar, E.LaChapelle, X.Hou, B.N.Rogers, J.Pandit, R.Lira, L.Martinez-Alsina, P.Mikochik, J.C.Murray, K.Ogilvie, L.Price, S.M.Sakya, A.Yu, Y.Zhang, B.T.O'Neill.

ABSTRACT

In recent years, the first generation of β-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 analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.