Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds,Journal of Medicinal Chemistry

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Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-07-23 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00760
Ewgenij Proschak ₁ , Holger Stark ₂ , Daniel Merk _{1,

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Affiliation

Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or the metabolic syndrome. Polypharmacological drug profiles can produce additive or synergistic effects while reducing side effects and significantly contribute to the high therapeutic success of indispensable drugs such as aspirin. While their identification has long been the result of serendipity, medicinal chemistry now tends to design polypharmacology. Modern in vitro pharmacological methods and chemical probes allow a systematic search for rational target combinations and recent innovations in computational technologies, crystallography, or fragment-based design equip multitarget compound development with valuable tools. In this Perspective, we analyze the relevance of multiple ligands in drug discovery and the versatile toolbox to design polypharmacology. We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential to secure future therapeutic innovation.

中文翻译：

设计上的多元药理学：药物化学家对多靶标化合物的看法

由于诸如癌症，炎症或代谢综合症等多因素疾病的复杂性，对一个以上生物学目标具有活性的多目标化合物在药物开发中已获得了显着的相关性。多药理学药物特性可以产生加成或协同作用，同时减少副作用，并显着促进不可或缺的药物（如阿司匹林）的高治疗成功率。尽管它们的鉴定长期以来是偶然性的结果，但药物化学现在倾向于设计多药理学。现代的体外药理方法和化学探针可以系统地搜索合理的靶标组合，并且可以在计算技术，晶体学或基于片段的设计中进行创新，从而为多靶标化合物的开发提供有价值的工具。在此观点中，我们分析了多种配体在药物发现中的相关性以及设计多元药理学的多功能工具箱。我们得出的结论是，尽管仍未解决某些特征性挑战，但设计的多药理学仍具有确保未来治疗创新的巨大潜力。

更新日期：2018-07-23

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