Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery
| Autor: | Fabien Lecomte, Francesca Toselli, William R. Pitt, Lloyd King, Nenad Manevski |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Drug
media_common.quotation_subject Drug design Computational biology 01 natural sciences Effective solution 03 medical and health sciences Metabolic Diseases Drug Discovery Animals Humans Enzyme Inhibitors Aldehyde oxidase 030304 developmental biology media_common 0303 health sciences Chemistry Drug discovery Metabolism 0104 chemical sciences Aldehyde Oxidase 010404 medicinal & biomolecular chemistry Pharmaceutical Preparations Drug Design Molecular Medicine Experimental methods Chemical design |
| Zdroj: | Journal of medicinal chemistry. 62(24) |
| ISSN: | 1520-4804 |
| Popis: | Aldehyde oxidase (AO) catalyzes oxidations of azaheterocycles and aldehydes, amide hydrolysis, and diverse reductions. AO substrates are rare among marketed drugs, and many candidates failed due to poor pharmacokinetics, interspecies differences, and adverse effects. As most issues arise from complex and poorly understood AO biology, an effective solution is to stop or decrease AO metabolism. This perspective focuses on rational drug design approaches to modulate AO-mediated metabolism in drug discovery. AO biological aspects are also covered, as they are complementary to chemical design and important when selecting the experimental system for risk assessment. The authors' recommendation is an early consideration of AO-mediated metabolism supported by computational and in vitro experimental methods but not an automatic avoidance of AO structural flags, many of which are versatile and valuable building blocks. Preferably, consideration of AO-mediated metabolism should be part of the multiparametric drug optimization process, with the goal to improve overall drug-like properties. |
| Databáze: | OpenAIRE |
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