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.

中文翻译：

---

通过系统开发构象集合探索 PQ912 与分泌型谷氨酰胺环化酶的结合模式

分泌型谷氨酰胺环化酶 (sQC) 在焦谷氨酸-淀粉样蛋白 β (pGlu-Aβ) 肽的形成中发挥重要作用，这是在阿尔茨海默病 (AD) 脑中发现的最丰富的 Aβ 变体之一。与野生型 Aβ (WT-Aβ) 相比，这种翻译后修饰的 pGlu-Aβ 具有高毒性和快速聚集倾向。由于 pGlu-Aβ 作为 WT-Aβ 的种子，sQC 的抑制限制了 pGlu-Aβ 的形成并降低了 AD 脑中 Aβ 斑块的总体负荷。PQ912是sQC的强效抑制剂，已进入AD药物研发管线的2b期临床试验；然而，PQ912 与 sQC 的结合模式尚未阐明。了解 PQ912 的绑定模式很重要，因为它有助于发现以 sQC 作为目标的 AD。探索PQ912的结合方式，我们对 9 个在活性位点几何形状或结合配体中不同的 sQC 结构进行了整体对接。进一步的姿势聚类和结合能计算为 PQ912 产生了三种可能的结合模式。最后，所有原子分子动力学模拟确定了 PQ912 在 sQC 的活性位点中最有利的结合模式，这与 LSB-09 相似，LSB-09 是一种最近报道的含有苯并咪唑-6-甲酰胺部分的 sQC 抑制剂。