PDBsum entry 7bgc

Hydrolase

PDB id: 7bgc

Contents

Protein chain

527 a.a.

Ligands

NAG-NAG-MAN-MAN-FUC

GAL-SIA

NAG-NAG-FUC ×2

TKN

NAG ×3

MES

GOL

SO4 ×3

Metals

_CL ×3

Waters ×90

PDB id:

7bgc

Name:

Hydrolase

Title:

Human butyrylcholinesterase in complex with a tacrine-methylanacardate hybrid inhibitor

Structure:

Cholinesterase. Chain: a. Synonym: acylcholine acylhydrolase,butyrylcholine esterase,choline esterase ii,pseudocholinesterase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bche, che1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: cho k1

Resolution:

2.40Å R-factor: 0.205 R-free: 0.247

Authors:

F.Nachon,A.Salerno,M.L.Bolognesi

Key ref:

M.Rossi et al. (2021). Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease. J Med Chem, 64, 4972-4990. PubMed id: 33829779 DOI: 10.1021/acs.jmedchem.1c00048

Date:

06-Jan-21 Release date: 28-Apr-21

Protein chain

P06276  (CHLE_HUMAN) -  Cholinesterase from Homo sapiens

Seq: 602 a.a.

Struc: 527 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.1.8 - cholinesterase.
• Reaction: an acylcholine + H2O = a carboxylate + choline + H⁺

acylcholine (Bound ligand (Het Group name = MES) matches with 46.67% similarity) + H2O = carboxylate + choline + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.1c00048

J Med Chem 64:4972-4990 (2021)

PubMed id: 33829779

Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease.

M.Rossi, M.Freschi, L.de Camargo Nascente, A.Salerno, S.de Melo Viana Teixeira, F.Nachon, F.Chantegreil, O.Soukup, L.Prchal, M.Malaguti, C.Bergamini, M.Bartolini, C.Angeloni, S.Hrelia, L.A.Soares Romeiro, M.L.Bolognesi.

ABSTRACT

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 μM), confirming the design rationale.