Exploring the binding mode of PQ912 against secretory glutaminyl cyclase through systematic exploitation of conformational ensembles

• Published in: Chemical biology & drug design 2021-11, Vol.98 (5), p.850-856
• Main Authors: Chandran, Remya, Dileep, Kalarickal V.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Amino Acid Sequence; Aminoacyltransferases - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Catalytic Domain; ensemble docking; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Imidazolines - chemistry; Imidazolines - pharmacology; Molecular Docking Simulation; Molecular Dynamics Simulation; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; PQ912; Protein Binding; Protein Conformation; Pyrrolidonecarboxylic Acid - chemistry; secretory glutaminyl cyclase; Structure-Activity Relationship; varoglutamstat
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13940

Secretory glutaminyl cyclase (sQC) plays an important role in the formation of the pyroglutamate‐amyloid beta (pGlu‐Aβ) peptide, one of the most abundant variants of Aβ found in the Alzheimer's disease (AD) brain. This post‐translationally modified pGlu‐Aβ possesses high toxicity and rapid aggregation propensity when compared to the wild‐type Aβ (WT‐Aβ). Since pGlu‐Aβ acts as seed for WT‐Aβ, the inhibition of sQC limits the formation of pGlu‐Aβ and reduces the overall load of Aβ 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. Binding of PQ912 with secretory glutaminyl cyclase.