Discovery of potent α‐glucosidase inhibitors through structure‐based virtual screening of an in‐house azole collection,Chemical Biology & Drug Design

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Discovery of potent α‐glucosidase inhibitors through structure‐based virtual screening of an in‐house azole collection
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-10-26 , DOI: 10.1111/cbdd.13805
Suat Sari ₁ , Burak Barut ₂ , Arzu Özel _{2,

3} , Selma Saraç ₁

Affiliation

Diabetes mellitus, a chronic disorder characterized by hyperglycemia, is considered a pandemic of modern times. α‐Glucosidase inhibitors emerged as a promising class of antidiabetic drugs with better tolerability compared with its alternatives. Azoles, although widely preferred in drug design, have scarcely been investigated for their potential against α‐glucosidase. In this study, we evaluated α‐glucosidase inhibitory effects 20 azole derivatives selected out of an in‐house collection via structure‐based virtual screening (VS) with consensus scoring approach. Seven compounds were identified with better IC₅₀ values than acarbose (IC₅₀ = 68.18 ± 1.01 µM), a well‐known α‐glucosidase inhibitor drug, which meant 35% success for our VS methodology. Compound 52, 54, 56, 59, and 81 proved highly potent with IC₅₀ values in the range of 40–60 µM. According to the enzyme kinetics study, four of them were competitive, 56 was non‐competitive inhibitor. Structure‐activity relationships, quantum mechanical, and docking analyses showed that azole rings at ionized state may be key to the potency observed for the active compounds and modifications to shift the balance between the neutral and ionized states further to the latter could yield more potent derivatives.

中文翻译：

通过内部唑类藏品的基于结构的虚拟筛选发现有效的α-葡萄糖苷酶抑制剂

糖尿病是一种以高血糖为特征的慢性疾病，被认为是现代流行病。α-葡萄糖苷酶抑制剂成为一类有前途的抗糖尿病药物，与其替代品相比具有更好的耐受性。唑类虽然在药物设计中被广泛采用，但几乎没有研究过它们对抗 α-葡萄糖苷酶的潜力。在这项研究中，我们通过基于结构的虚拟筛选 (VS) 和共识评分方法评估了从内部收集中选出的 20 种唑类衍生物的 α-葡萄糖苷酶抑制作用。鉴定出七种化合物的 IC ₅₀值优于阿卡波糖 (IC ₅₀ = 68.18 ± 1.01 µM)，这是一种众所周知的 α-葡萄糖苷酶抑制剂药物，这意味着我们的 VS 方法成功率为 35%。化合物52 ,54，56，59，和81证明了与IC高度有效₅₀在40-60微米范围内的值。根据酶动力学研究，其中 4 个是竞争性的，56 个是非竞争性抑制剂。构效关系、量子力学和对接分析表明，电离状态的唑环可能是观察到的活性化合物效力的关键，而将中性和电离状态之间的平衡进一步转移到后者的修饰可以产生更有效的衍生物.

更新日期：2020-10-26

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