PMID- 33876698
OWN - NLM
STAT- MEDLINE
DCOM- 20221018
LR  - 20221202
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
VI  - 40
IP  - 18
DP  - 2022 Nov
TI  - Binding of hydroxychloroquine and chloroquine dimers to palmitoyl-protein 
      thioesterase 1 (PPT1) and its glycosylated forms: a computational approach.
PG  - 8197-8205
LID - 10.1080/07391102.2021.1908167 [doi]
AB  - 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 (DeltaE), 
      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.Communicated by Ramaswamy H. Sarma.
FAU - Vergoten, Gerard
AU  - Vergoten G
AD  - Inserm, INFINITE - U1286, Institut de Chimie Pharmaceutique Albert Lespagnol 
      (ICPAL), Faculte de Pharmacie, University of Lille, Lille, France.
FAU - Bailly, Christian
AU  - Bailly C
AUID- ORCID: 0000-0002-2973-9357
AD  - OncoWitan, Lille (Wasquehal), France.
LA  - eng
PT  - Journal Article
DEP - 20210420
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - 0 (Fatty Acids)
RN  - 0 (Membrane Proteins)
RN  - 0 (Palmitates)
RN  - 4QWG6N8QKH (Hydroxychloroquine)
RN  - 7006-34-0 (Asparagine)
RN  - 886U3H6UFF (Chloroquine)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Asparagine
MH  - Child
MH  - Chloroquine
MH  - Fatty Acids
MH  - Humans
MH  - Hydroxychloroquine/pharmacology
MH  - Membrane Proteins/metabolism
MH  - *Neoplasms
MH  - *Neuronal Ceroid-Lipofuscinoses/drug therapy/genetics/metabolism
MH  - Palmitates
MH  - Thiolester Hydrolases
OTO - NOTNLM
OT  - PPT1
OT  - drug-protein binding
OT  - hydroxychloroquine
OT  - molecular modeling
OT  - palmitoylated proteins
EDAT- 2021/04/21 06:00
MHDA- 2022/10/19 06:00
CRDT- 2021/04/20 08:47
PHST- 2021/04/21 06:00 [pubmed]
PHST- 2022/10/19 06:00 [medline]
PHST- 2021/04/20 08:47 [entrez]
AID - 10.1080/07391102.2021.1908167 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2022 Nov;40(18):8197-8205. doi: 
      10.1080/07391102.2021.1908167. Epub 2021 Apr 20.