PDBsum entry 6i0c

Hydrolase

PDB id: 6i0c

Contents

Protein chain

526 a.a.

Ligands

NAG-FUC

NAG-NAG-FUC ×2

NAG ×3

MES

GZ5

SO4 ×4

Metals

_NA

Waters ×56

PDB id:

6i0c

Name:

Hydrolase

Title:

Human butyrylcholinesterase in complex with the r enantiomer of a chlorotacrine-tryptophan multi-target inhibitor.

Structure:

Cholinesterase. Chain: a. Synonym: acylcholine acylhydrolase,butyrylcholine esterase,choline esterase ii,pseudocholinesterase. Engineered: yes. Mutation: yes. Other_details: nags and fucs are glycosylations

Source:

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

Resolution:

2.68Å R-factor: 0.193 R-free: 0.252

Authors:

X.Brazzolotto,F.Nachon

Key ref:

K.Chalupova et al. (2019). Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease. Eur J Med Chem, 168, 491-514. PubMed id: 30851693 DOI: 10.1016/j.ejmech.2019.02.021

Date:

25-Oct-18 Release date: 27-Mar-19

Protein chain

P06276  (CHLE_HUMAN) -  Cholinesterase from Homo sapiens

Seq: 602 a.a.

Struc: 526 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: 10.1016/j.ejmech.2019.02.021

Eur J Med Chem 168:491-514 (2019)

PubMed id: 30851693

Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease.

K.Chalupova, J.Korabecny, M.Bartolini, B.Monti, D.Lamba, R.Caliandro, A.Pesaresi, X.Brazzolotto, A.J.Gastellier, F.Nachon, J.Pejchal, M.Jarosova, V.Hepnarova, D.Jun, M.Hrabinova, R.Dolezal, J.Zdarova Karasova, M.Mzik, Z.Kristofikova, J.Misik, L.Muckova, P.Jost, O.Soukup, M.Benkova, V.Setnicka, L.Habartova, M.Chvojkova, L.Kleteckova, K.Vales, E.Mezeiova, E.Uliassi, M.Valis, E.Nepovimova, M.L.Bolognesi, K.Kuca.

ABSTRACT

A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC₅₀ values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ₄₂ self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ₄₀ aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.