4TPK

Human butyrylcholinesterase in complex with N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide

Summary for 4TPK

• Entry DOI: 10.2210/pdb4tpk/pdb
• Related: 4BDS
• Descriptor: Cholinesterase, beta-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: butyrylcholinesterase inhibition, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 143427.96

Authors

Coquelle, N.,Brus, B.,Colletier, J.P.,Gobec, S. (deposition date: 2014-06-07, release date: 2014-10-22, Last modification date: 2024-10-23)

Primary citation

Brus, B.,Kosak, U.,Turk, S.,Pislar, A.,Coquelle, N.,Kos, J.,Stojan, J.,Colletier, J.P.,Gobec, S.
Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor.
J.Med.Chem., 57:8167-8179, 2014

PubMed Abstract: Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally, compound 1 inhibited amyloid β(1-42) peptide self-induced aggregation into fibrils (by 61.7% at 10 μM) and protected cultured SH-SY5Y cells against amyloid-β-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease.

PubMed: 25226236
DOI: 10.1021/jm501195e

Experimental method

X-RAY DIFFRACTION (2.7 Å)