Titre :

Binding of hydroxychloroquine and chloroquine dimers to palmitoyl-protein thioesterase 1 (PPT1) and its glycosylated forms: a computational approach.

Auteur(s) :

Vergoten, Gerard [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE]
Bailly, Christian [Auteur]
Oncowitan [Wasquehal]

Titre de la revue :

Journal of Biomolecular Structure and Dynamics

Nom court de la revue :

J Biomol Struct Dyn

Numéro :

40

Pagination :

8197-8205

Éditeur :

Taylor & Francis Online

Date de publication :

2021-04-22

ISSN :

1538-0254

Mot(s)-clé(s) en anglais :

PPT1
hydroxychloroquine
palmitoylated proteins
drug-protein binding
molecular modeling

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

The lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) removes thioester-linked fatty acid groups from membrane-bound proteins to facilitate their proteolysis. A lack of PPT1 (due to gene mutations) causes the ...
Lire la suite >The lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) removes thioester-linked fatty acid groups from membrane-bound proteins to facilitate their proteolysis. A lack of PPT1 (due to gene mutations) causes the progressive death of cortical neurons and is responsible for infantile neural ceroid lipofuscinosis (INCL), a severe neurodegenerative disorder in children. Conversely, PPT1 is often over-expressed in cancer, and considered as a valid target to control tumor growth. Potent and selective inhibitors of PPT1 have been designed, in particular 4-amino-7-chloro-quinoline derivatives such as hydroxychloroquine (HCQ) and the dimeric analogues Lys05 and DC661. We have modeled the interaction of these three compounds with the enzyme, taking advantage of the PPT1 crystallographic structure. The molecules can fit into the palmitate site of the protein, with the dimeric compounds forming more stable complexes than the monomer. But the molecular modeling suggests that the most favorable binding sites are located outside the active site. Two sites centered on residues Met112 and Gln144 were identified, offering suitable cavities for drug binding. According to the calculated empirical energies of interaction (ΔE), the dimer DC661 forms the most stable complex at site Met112 of palmitate-bound PPT1. N-glycosylated forms of PPT1 were elaborated. Paucimannosidic glycans (M2FA and M3F) and a bulkier tetra-antennary complex glycan were introduced at asparagine residues N197, N212 and N232. These N-glycans do not impede drug binding, thus suggesting that all glycoforms of PPT1 can be targeted with these compounds.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Date de dépôt :

2025-03-14T22:12:00Z
2025-03-26T10:02:32Z