4IVT

Crystal structure of BACE1 with its inhibitor

Summary for 4IVT

• Entry DOI: 10.2210/pdb4ivt/pdb
• Related: 4IVS
• Descriptor: Beta-secretase 1, N-{N-[4-(acetylamino)-3,5-dichlorobenzyl]carbamimidoyl}-2-(1H-indol-1-yl)acetamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 48847.35

Authors

Chen, T.T.,Li, L.,Chen, W.Y.,Xu, Y.C. (deposition date: 2013-01-23, release date: 2013-11-13, Last modification date: 2024-10-30)

Primary citation

Zou, Y.,Li, L.,Chen, W.Y.,Chen, T.T.,Ma, L.,Wang, X.,Xiong, B.,Xu, Y.C.,Shen, J.
Virtual screening and structure-based discovery of indole acylguanidines as potent beta-secretase (BACE1) inhibitors
Molecules, 18:5706-5722, 2013

PubMed Abstract: Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.

PubMed: 23681056
DOI: 10.3390/molecules18055706

Experimental method

X-RAY DIFFRACTION (1.6 Å)