Identifying Substructures That Facilitate Compounds to Penetrate the Blood–Brain Barrier via Passive Transport Using Machine Learning Explainer Models

Article

作者: Rosa, Lucca Caiaffa Santos ; Nascimento, Cayque Monteiro Castro ; Pimentel, Andre Silva ; Argolo, Caio Oliveira

The local interpretable model-agnostic explanation (LIME) method was used to interpret two machine learning models of compounds penetrating the blood-brain barrier. The classification models, Random Forest, ExtraTrees, and Deep Residual Network, were trained and validated using the blood-brain barrier penetration dataset, which shows the penetrability of compounds in the blood-brain barrier. LIME was able to create explanations for such penetrability, highlighting the most important substructures of molecules that affect drug penetration in the barrier. The simple and intuitive outputs prove the applicability of this explainable model to interpreting the permeability of compounds across the blood-brain barrier in terms of molecular features. LIME explanations were filtered with a weight equal to or greater than 0.1 to obtain only the most relevant explanations. The results showed several structures that are important for blood-brain barrier penetration. In general, it was found that some compounds with nitrogenous substructures are more likely to permeate the blood-brain barrier. The application of these structural explanations may help the pharmaceutical industry and potential drug synthesis research groups to synthesize active molecules more rationally.

Iyakuhin Kenkyu

Toxicity of (+)-9α-fluoro-11β-hydroxy-21-methoxy-16β-methyl-17α-propionyloxy-1,4-pregnadiene-3,20-dione (TS-410) (III). Twenty-six-week percutaneous toxicity study in rats

作者: Tarumoto, Yasuo ; Tanaka, Rika ; Kimura, Masaaki ; Tsuchida, Takeshi ; Kasai, Akira

The chronic toxicity of a new synthetic corticosteroid, TS-410, was investigated in rats of both sexes.TS-410 was administered percutaneously at 0.000125, 0.0025, 0.05, and 1.0 mg/kg/day for 26 wk.A 4-wk recovery test was performed on the animals given the 2 highest doses.No deaths occurred during the trial period.The changes observed were the well-known toxic effects of synthetic corticosteroids, and these had almost disappeared after a recovery time of 4 wk following the withdrawal of TS-410.It is suggested that the maximum non-toxic dose of TS-410 under the conditions of this study was 0.0025 mg/kg.

Iyakuhin Kenkyu

Reproductive and developmental toxicity studies of (+)-9α-fluoro-11β-hydroxy-21-methoxy-16β-methyl-17α-propionyloxy-1,4-pregnadiene-3,20-dione (TS-410) (III). Teratogenicity study in rabbits

作者: Uchiyama, Hisashi ; Naitoh, Yuichi ; Tarumoto, Yasuo ; Suzuki, Toshiro ; Yamada, Takashi ; Inoue, Tadahiro

(+)-9α-Fluoro-11β-hydroxy-21-methoxy-16β-methyl-17α-propionyloxy-1,4-pregnadiene-3,20-dione (TS-410), a new synthetic adrenocorticosteroid, was administered s.c. at doses of 0.002, 0.004 or 0.008 mg/kg to New Zealand White rabbits (Std: NZW) during the period of fetal organogenesis (days 6 to 18 of gestation) to examine its effects on dams and their fetuses.In dams, no deaths were noted in any of the treated groups.However, the highest dose of 0.008 mg/kg induced abortion in a few animals and suppressed body weight gain.In fetuses, lethality, suppression of growth and teratogenic effects were noted in the 0.008 mg/kg group.Also, a weak teratogenic effect appeared to be present in the 0.004 mg/kg group.These findings suggested that the maximum no-effect dose of TS-410 was 0.004 mg/kg for dams and 0.002 mg/kg for fetuses.

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KEGG	Wiki	ATC	Drug Bank
D01156	Amelometasone	-	-

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适应症	最高研发状态	国家/地区	公司	日期
皮炎	申请上市	日本	Taisho Pharmaceutical Co., Ltd.	1996-03-01
皮肤疾病	申请上市	日本	-	-
皮肤疾病	申请上市	-	Taisho Pharmaceutical Holdings Co., Ltd.	-