Metabolism of a New Antiaggregant, Indolinone Derivative

Bykov, V. V.; Leonov, Klim A.; Serebrov, V. Yu.; Чернышева, Г. А.; Smol’yakova, V. I.; Solov’ev, M. A.; Удут, Е. В.; Фисенко, Владимир Петрович; Удут, В. В.

doi:10.1007/s10517-020-04792-y

Cited by 2 publications

(1 citation statement)

References 5 publications

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“…HumanP450Test1 comprised experimentally verified 65 CYP-substrate pairs and 15 CYP-nonsubstrate pairs described in the latest literature published between 2018 and 2023, and the CYPs in this data set refer to the nine categories of CYPs in the TrainSet. − The distribution of Tanimoto Similarity coefficients for small molecules in HumanP450Test1 and the TrainSet is shown in Figure A. Both the t-SNE plot (Figure D) and the similarity distribution indicated that 58% molecules in HumanP450Test1 exhibited similarity values lower than 0.5, with no instances of similarity reaching 0.9 or higher.…”

Section: Resultsmentioning

confidence: 99%

DeepP450: Predicting Human P450 Activities of Small Molecules by Integrating Pretrained Protein Language Model and Molecular Representation

Chang,

Fan,

Tian

2024

J. Chem. Inf. Model.

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Cytochrome P450 enzymes (CYPs) play a crucial role in Phase I drug metabolism in the human body, and CYP activity toward compounds can significantly affect druggability, making early prediction of CYP activity and substrate identification essential for therapeutic development. Here, we established a deep learning model for assessing potential CYP substrates, DeepP450, by fine-tuning protein and molecule pretrained models through feature integration with cross-attention and self-attention layers. This model exhibited high prediction accuracy (0.92) on the test set, with area under the receiver operating characteristic curve (AUROC) values ranging from 0.89 to 0.98 in substrate/nonsubstrate predictions across the nine major human CYPs, surpassing current benchmarks for CYP activity prediction. Notably, DeepP450 uses only one model to predict substrates/nonsubstrates for any of the nine CYPs and exhibits certain generalizability on novel compounds and different categories of human CYPs, which could greatly facilitate early stage drug design by avoiding CYP-reactive compounds.

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Section: Resultsmentioning

confidence: 99%

DeepP450: Predicting Human P450 Activities of Small Molecules by Integrating Pretrained Protein Language Model and Molecular Representation

Chang,

Fan,

Tian

2024

J. Chem. Inf. Model.

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Distribution and Transmembrane transport as the basis of proper Pharmacodynamics of an Antithrombotic drug – An Indolinone derivative

Valer’evich¹,

Vladimirovna

Andreevich³

et al. 2022

RJPT

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The goal of the present study: assess the distribution and transmembrane transport of an antiaggregant drug GRS of indolinone series. The distribution of an indolinone derivative in organs, between blood plasma and blood cells was studied in Sprague Dawley rats. A Thermo Scientific Pierce dialysis system was used to study the binding to blood plasma proteins. A MultiScreen Caco-2 test system was used to study the transmembrane transfer of the indolinone derivative. Quantitative assay of GRS was performed by an HPLC/МS method. GRS was shown to pass into the liver, heart and kidneys, and doesn’t pass into the brain and skeletal muscle. The highest GRS accumulation occurs in the liver, the lowest in the kidneys. GRS has low plasma protein binding and its concentration is 1.6 times higher in blood cells than in blood plasma. GRS in 1 mcmol concentration has low cell membrane permeability from apical to basolateral membrane (A-B), increasing the concentration gradient by 10 times leads to a corresponding increase in transport efficiency. In the reverse direction (B-A) GRS permeability is 8.8 times higher, showing its participation in active transport. Pgp inhibitor cyclosporin A considerably decreases the transport efficiency of GRS in B-A direction.

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Metabolism of a New Antiaggregant, Indolinone Derivative

Cited by 2 publications

References 5 publications

DeepP450: Predicting Human P450 Activities of Small Molecules by Integrating Pretrained Protein Language Model and Molecular Representation

DeepP450: Predicting Human P450 Activities of Small Molecules by Integrating Pretrained Protein Language Model and Molecular Representation

Distribution and Transmembrane transport as the basis of proper Pharmacodynamics of an Antithrombotic drug – An Indolinone derivative

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