Exploring the binding mode of PQ912 against secretory glutaminyl cyclase through systematic exploitation of conformational ensembles.
Chem Biol Drug Des
; 98(5): 850-856, 2021 11.
Article
em En
| MEDLINE
| ID: mdl-34423556
ABSTRACT
Secretory glutaminyl cyclase (sQC) plays an important role in the formation of the pyroglutamate-amyloid beta (pGlu-Aß) peptide, one of the most abundant variants of Aß found in the Alzheimer's disease (AD) brain. This post-translationally modified pGlu-Aß possesses high toxicity and rapid aggregation propensity when compared to the wild-type Aß (WT-Aß). Since pGlu-Aß acts as seed for WT-Aß, the inhibition of sQC limits the formation of pGlu-Aß and reduces the overall load of Aß plaques in the AD brain. PQ912 is a potent inhibitor of sQC and has been enrolled in phase 2b clinical trial of the AD drug development pipeline; however, the binding mode of PQ912 against sQC is not elucidated yet. Understanding the binding mode of PQ912 is important as it helps in the discovery against AD where sQC as a target. To explore the binding mode of PQ912, we employed ensemble docking towards 9 sQC structures that differ either in active site geometry or in the bound ligands. Further pose clustering and binding energy calculations yielded three possible binding modes for PQ912. Finally, all atom molecular dynamics simulations determined the most energetically favorable binding mode for PQ912, in the active site of sQC, which is similar to that of LSB-09, a recently reported sQC inhibitor containing benzimidazole-6-carboxamide moiety.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
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Peptídeos beta-Amiloides
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Fármacos Neuroprotetores
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Aminoaciltransferases
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Imidazolinas
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Inibidores Enzimáticos
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Doença de Alzheimer
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article