Small-Scale Panel Comprising Diverse Gene Family Targets To Evaluate Compound Promiscuity
| Autor: | Taisuke Katoh, Tomoya Sameshima, Masato Yoshikawa, Tomoya Yukawa, Hideto Hara, Takatoshi Yogo, Russell Naven, Makoto Miyamoto, Ikuo Miyahisa, Yoshihiko Hirozane, Teruaki Okuda |
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| Rok vydání: | 2019 |
| Předmět: |
Drug
Drug-Related Side Effects and Adverse Reactions Cell Survival media_common.quotation_subject Drug Evaluation Preclinical 010501 environmental sciences Biology Toxicology Bioinformatics 01 natural sciences Mice 03 medical and health sciences Receptors Glucocorticoid Receptor Serotonin 5-HT2B Animals Humans Gene family Adverse effect 030304 developmental biology 0105 earth and related environmental sciences media_common rho-Associated Kinases 0303 health sciences Drug discovery Receptor Adenosine A3 Receptor Muscarinic M1 Biological activity Hep G2 Cells General Medicine Receptors GABA-A Cyclic Nucleotide Phosphodiesterases Type 4 Rats PPAR gamma Promiscuity Drug development Toxicity |
| Zdroj: | Chemical Research in Toxicology. 33:154-161 |
| ISSN: | 1520-5010 0893-228X |
| Popis: | Despite the recent advances in the life sciences and the remarkable investment in drug discovery research, the success rate of small-molecule drug development remains low. Safety is the second most influential factor of drug attrition in clinical studies; thus, the selection of compounds with fewer toxicity concerns is crucial to increase the success rate of drug discovery. Compounds that promiscuously bind to multiple targets are likely to cause unexpected pharmacological activity that may lead to adverse effects. Therefore, avoiding such compounds during early research stages would contribute to identifying compounds with a higher chance of success in the clinic. To evaluate the interaction profile against a wide variety of targets, we constructed a small-scale promiscuity panel (PP) consisting of eight targets (ROCK1, PDE4D2, GR, PPARγ, 5-HT2B, adenosine A3, M1, and GABAA) that were selected from diverse gene families. The validity of this panel was confirmed by comparison with the promiscuity index evaluated from larger-scale panels. Analysis of data from the PP revealed that both lipophilicity and basicity are likely to increase promiscuity, while the molecular weight does not significantly contribute. Additionally, the promiscuity assessed using our PP correlated with the occurrence of both in vitro cytotoxicity and in vivo toxicity, suggesting that the PP is useful to identify compounds with fewer toxicity concerns. In summary, this small-scale and cost-effective PP can contribute to the identification of safer compounds that would lead to a reduction in drug attrition due to safety issues. |
| Databáze: | OpenAIRE |
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