PDBsum entry 4fsl

Hydrolase/inhibitor

PDB id: 4fsl

Contents

Protein chains

387 a.a.

Ligands

0VB ×4

Metals

IOD ×12

Waters ×819

PDB id:

4fsl

Name:

Hydrolase/inhibitor

Title:

Crystal structure of beta-site app-cleaving enzyme 1 (bace-db-mut) complex with n-(n-(4- acetamido-3-chloro-5-methylbenzyl) carbamimidoyl)-3-(4- methoxyphenyl)-5-methyl-4-isothiazolecarboxamide

Structure:

Beta-secretase 1. Chain: a, b, d, e. Fragment: unp residues 43-453. Synonym: aspartyl protease 2, asp2, asp 2, beta-site amyloid precursor protein cleaving enzyme 1, beta-site app cleaving enzyme 1, memapsin-2, membrane-associated aspartic protease 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.50Å R-factor: 0.227 R-free: 0.277

Authors:

J.K.Muckelbauer

Key ref:

S.W.Gerritz et al. (2012). Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis. J Med Chem, 55, 9208-9223. PubMed id: 23030502

Date:

27-Jun-12 Release date: 10-Oct-12

Protein chains

P56817  (BACE1_HUMAN) -  Beta-secretase 1 from Homo sapiens

Seq: 501 a.a.

Struc: 387 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.23.46 - memapsin 2.

J Med Chem 55:9208-9223 (2012)

PubMed id: 23030502

Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.

S.W.Gerritz, W.Zhai, S.Shi, S.Zhu, J.H.Toyn, J.E.Meredith, L.G.Iben, C.R.Burton, C.F.Albright, A.C.Good, A.J.Tebben, J.K.Muckelbauer, D.M.Camac, W.Metzler, L.S.Cook, R.Padmanabha, K.A.Lentz, M.J.Sofia, M.A.Poss, J.E.Macor, L.A.Thompson.

ABSTRACT

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aβ levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aβ levels were not obtained.