改善槲皮素类似物通过血脑屏障的渗透性的分子描述符主成分分析(PCA)

IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Molecular Sciences Pub Date : 2023-12-22 DOI:10.3390/ijms25010192
N. Pavlović, Nastasija Milošević Sopta, Darko Mitrović, D. Zaklan, Ana Tomas Petrović, N. Stilinović, S. Vukmirović
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引用次数: 0

摘要

尽管槲皮素在大脑中具有有益的药理作用(部分是通过调节肌醇磷酸多激酶(IPMK)的活性),但由于其溶解性差、口服生物利用度低以及通过血脑屏障(BBB)的渗透性低,槲皮素的治疗用途受到了限制。我们的目标是找出能改善 BBB 渗透性并保持与 IPMK 结合亲和力的槲皮素类似物,并找出它们渗透 BBB 所需的分子特征。通过分子对接确定了槲皮素类似物与 IPMK 的结合亲和力。应用主成分分析法(PCA)确定了有助于有效渗透 BBB 的分子描述因子。在34种槲皮素类似物中,发现有19种化合物能与IPMK形成更稳定的复合物,而且绝大多数化合物都比槲皮素更亲脂。利用两种不同的硅学技术,确定了所有槲皮素类似物的生物BB渗透性不足。然而,利用 PCA 方法,与内在溶解度和亲油性(logP)有关的描述因子被确定为导致四种槲皮素类似物(三羟基黄酮类化合物)的生物BB渗透性最高的主要原因。应用 PCA 发现,可以根据槲皮素类似物的结构特征对其进行分类,这可用于进一步的类似物合成以及作为神经保护剂的 BBB 穿透性 IPMK 调节剂的先导优化。
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Principal Component Analysis (PCA) of Molecular Descriptors for Improving Permeation through the Blood–Brain Barrier of Quercetin Analogues
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.
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来源期刊
International Journal of Molecular Sciences
International Journal of Molecular Sciences Chemistry-Organic Chemistry
CiteScore
8.10
自引率
10.70%
发文量
13472
审稿时长
17.49 days
期刊介绍: The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).
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