通过分子建模探讨阿卡波糖与人类肠道共生菌多形拟杆菌淀粉利用系统中淀粉酶SusG的相互作用机制,Chemical Biology & Drug Design

当前位置： X-MOL 学术 › Chem. Bio. Drug Des. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

通过分子建模探讨阿卡波糖与人类肠道共生菌多形拟杆菌淀粉利用系统中淀粉酶SusG的相互作用机制
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2023-04-16 , DOI: 10.1111/cbdd.14251
Samuel Kwain ₁ , Brian N. Dominy ₁ , Kristi J. Whitehead ₂ , Brock A. Miller ₁ , Daniel C. Whitehead ₁

Affiliation

α-淀粉酶 SusG 是多形拟杆菌( Bt ) 淀粉利用系统 (Sus) 的主要成分，用于代谢人类胃肠 (GI) 道中的复杂淀粉分子。我们之前报道过通过阿卡波糖介导的 Sus阻滞来抑制Bt的非杀菌性生长，作为一种潜在的治疗策略。在此，我们报告了一种利用密度泛函理论（DFT）、分子对接和分子动力学（MD）模拟的计算方法，在原子水平上探索阿卡波糖和SusG之间的相互作用机制，以了解阿卡波糖如何关闭Bt苏。对接分析表明阿卡波糖与 SusG 正位结合，结合亲和力为 -8.3 kcal/mol。MD模拟提供了阿卡波糖在SusG活性位点的构象变异性的证据，并且还表明阿卡波糖通过通用酸碱双置换催化机制与主要催化残基相互作用。这些结果表明，针对 SusG 蛋白的小分子竞争性抑制可能会影响整个Bt Sus，并消除或降低系统代谢淀粉的能力。这种计算策略可以作为基于结构的药物设计的潜在途径，以发现其他能够抑制 Bt Sus 的小分子具有高效力，从而为选择性调节胃肠道微生物群提供整体方法。

"点击查看英文标题和摘要"

Exploring the interactive mechanism of acarbose with the amylase SusG in the starch utilization system of the human gut symbiont Bacteroides thetaiotaomicron through molecular modeling

The α-amylase, SusG, is a principal component of the Bacteroides thetaiotaomicron (Bt) starch utilization system (Sus) used to metabolize complex starch molecules in the human gastrointestinal (GI) tract. We previously reported the non-microbicidal growth inhibition of Bt by the acarbose-mediated arrest of the Sus as a potential therapeutic strategy. Herein, we report a computational approach using density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulation to explore the interactive mechanism between acarbose and SusG at the atomic level in an effort to understand how acarbose shuts down the Bt Sus. The docking analysis reveals that acarbose binds orthosterically to SusG with a binding affinity of −8.3 kcal/mol. The MD simulation provides evidence of conformational variability of acarbose at the active site of SusG and also suggests that acarbose interacts with the main catalytic residues via a general acid–base double-displacement catalytic mechanism. These results suggest that small molecule competitive inhibition against the SusG protein could impact the entire Bt Sus and eliminate or reduce the system's ability to metabolize starch. This computational strategy could serve as a potential avenue for structure-based drug design to discover other small molecules capable of inhibiting the Sus of Bt with high potency, thus providing a holistic approach for selective modulation of the GI microbiota.

更新日期：2023-04-16

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南