In silico Prediction of ADMET/Drug-likeness Properties of Bioactive Phloroglucinols from Hypericum Genus.

IF 1.9 4区医学 Q3 CHEMISTRY, MEDICINAL Medicinal Chemistry Pub Date : 2023-01-01 DOI:10.2174/1573406419666230601092358

Camila Pires Machado da Silva, Gustavo Machado das Neves, Gilsane Lino von Poser, Vera Lucia Eifler-Lima, Stela Maris Kuze Rates

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Abstract

Background: Dimeric acylphloroglucinols occurring in species from sections Brathys and Trigynobrathys of the genus Hypericum exhibit acylfilicinic acid and acylphloroglucinol moieties linked by a methylene bridge. However, this chemical feature differs from hyperforin, from H. perforatum (Hypericum section). Some dimeric acylphloroglucinols, such as uliginosin B, display similar pharmacological activities, namely antidepressant and antinociceptive. However, there is no knowledge about the pharmacokinetic profile and no toxicity studies of these compounds in intact mammals.

Objective: To perform an in silico evaluation of the similarity, pharmacokinetics and toxicity (ADMET) properties of dimeric acylphloroglucinols from species native to Central and South America.

Methods: ADMET prediction of eleven elected phloroglucinols followed by the chemical space evaluation of thirty-five dimeric acylphloroglucinols derivatives labeled according to their prenylation/ geranylation pattern through principal component analysis (PCA). The similarity analysis was performed using the Tanimoto similarity index. ADMET properties were predicted with the opensource software SwissADME and pkCSM-pharmacokinetics.

Results: Several compounds showed good human intestinal absorption. However, they may present difficulties in crossing the blood-brain barrier, probably due to the high tPSA values. The predicted toxicity parameters indicated that most compounds have low toxicity. Most non-prenylated phloroglucinols were disposed into Lipinski's rule limits. Uliginosin B, isouliginosin B and japonicin A seem to be druglike compounds. The PCA model explained 77.49% of the total variance, and molecular similarity analyses revealed some expected similarities between isomers and different compounds.

Conclusion: Dimeric acylphloroglucinols may be promising drug candidates and deserve further pharmacological and medicinal chemistry studies.

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金丝桃属生物活性酚类化合物ADMET/药物相似性的计算机预测。

背景：金丝桃属Brathys和Triynobrathys属植物中存在的二聚酰基氯葡糖醇表现出酰基Filicinic acid和酰基氯葡糖醇部分通过亚甲基桥连接。然而，这种化学特征不同于金丝桃苷，也不同于穿孔莲（金丝桃科）。一些二聚酰基氯葡糖醇，如uliginosin B，显示出类似的药理活性，即抗抑郁和抗伤害感受。然而，目前还不了解这些化合物在完整哺乳动物中的药代动力学特征和毒性研究。目的：对相似性进行计算机评价，原产于中美洲和南美洲物种的二聚酰基氯苯酚的药代动力学和毒性（ADMET）特性。方法：对11种选定的间苯三酚进行ADMET预测，然后通过主成分分析（PCA）对35种根据其异戊二烯化/香叶基化模式标记的二聚酰氯苯酚衍生物进行化学空间评估。使用Tanimoto相似性指数进行相似性分析。利用开源软件SwissADME和pkCSM药物动力学预测了ADMET的性质。结果：几种化合物显示出良好的人体肠道吸收。然而，它们可能在跨越血脑屏障方面存在困难，这可能是由于tPSA值高。预测的毒性参数表明，大多数化合物具有低毒性。大多数非异戊二烯化的间苯三酚都被置于利平斯基规则的限制范围内。Uliginosin B、isouliginosin B和japonicin A似乎是类药物化合物。主成分分析模型解释了77.49%的总方差，分子相似性分析揭示了异构体和不同化合物之间的一些预期相似性。结论：二聚酰基氯三酚可能是一种有前景的候选药物，值得进一步的药理和药物化学研究。

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来源期刊

Medicinal Chemistry 医学-医药化学

CiteScore

4.30

自引率

4.30%

发文量

109

审稿时长

12 months

期刊介绍： Aims & Scope Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.