Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
Accelsiors CRO, Háros Street 103, 1222 Budapest, Hungary.
Int J Mol Sci. 2023 Dec 22;25(1):192. doi: 10.3390/ijms25010192.
Despite its beneficial pharmacological effects in the brain, partly by modulating inositol phosphate multikinase (IPMK) activity, the therapeutic use of quercetin is limited due to its poor solubility, low oral bioavailability, and low permeability through the blood-brain barrier (BBB). We aimed to identify quercetin analogues with improved BBB permeability and preserved binding affinities towards IPMK and to identify the molecular characteristics required for them to permeate the BBB. Binding affinities of quercetin analogues towards IPMK were determined by molecular docking. Principal component analysis (PCA) was applied to identify the molecular descriptors contributing to efficient permeation through the BBB. Among 34 quercetin analogues, 19 compounds were found to form more stable complexes with IPMK, and the vast majority were found to be more lipophilic than quercetin. Using two distinct in silico techniques, insufficient BBB permeation was determined for all quercetin analogues. However, using the PCA method, the descriptors related to intrinsic solubility and lipophilicity (logP) were identified as mainly responsible for clustering four quercetin analogues (trihydroxyflavones) with the highest BBB permeability. The application of PCA revealed that quercetin analogues could be classified with respect to their structural characteristics, which may be utilized in further analogue syntheses and lead optimization of BBB-penetrating IPMK modulators as neuroprotective agents.
尽管槲皮素在大脑中有有益的药理作用，部分是通过调节肌醇磷酸多激酶（IPMK）的活性，但由于其溶解度低、口服生物利用度低以及通过血脑屏障（BBB）的通透性低，其治疗用途受到限制。我们旨在确定具有改善的 BBB 通透性的槲皮素类似物，并保留对 IPMK 的结合亲和力，并确定它们穿透 BBB 所需的分子特征。通过分子对接确定槲皮素类似物对 IPMK 的结合亲和力。应用主成分分析（PCA）来确定有助于有效穿透 BBB 的分子描述符。在 34 种槲皮素类似物中，发现 19 种化合物与 IPMK 形成更稳定的复合物，并且绝大多数比槲皮素更亲脂。使用两种不同的计算技术，发现所有槲皮素类似物都不能充分穿透 BBB。然而，使用 PCA 方法，确定了与固有溶解度和脂溶性（logP）相关的描述符是主要负责将四个具有最高 BBB 通透性的槲皮素类似物（三羟基黄酮）聚类的原因。PCA 的应用表明，槲皮素类似物可以根据其结构特征进行分类，这可能用于进一步的类似物合成和作为神经保护剂的穿透 BBB 的 IPMK 调节剂的先导优化。
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