To combat multifactorial refractory diseases, such as cancer, cardiovascular, and neurodegenerative diseases, multitarget drugs have become an emerging area of research aimed at ‘synthetic lethality’ (SL) relationships associated with drug-resistance mechanisms. In this review, we discuss the design of dual and triple-targeted ligands, strategies by which specific ‘warhead’ groups are incorporated into a parent compound or scaffold with primary inhibitory activity against one target to develop one small molecule that inhibits two or three molecular targets in an effort to increase potency against multifactorial diseases. We also discuss the analytical exploration of structure–activity relationships (SARs), physicochemical properties, polypharmacology, scaffold feature extraction of US Food and Drug Administration (FDA)-approved multikinase inhibitors (MKIs), and updates regarding the clinical status of dual-targeted chemotypes.

中文翻译：

---

通过计算机药物发现在多靶点定向配体方面的最新进展


为了对抗癌症、心血管和神经退行性疾病等多因素难治性疾病，多靶点药物已成为一个新兴的研究领域，旨在研究与耐药机制相关的“综合致死”（SL）关系。在这篇综述中，我们讨论了双靶点和三靶点配体的设计，以及将特定“弹头”基团整合到对一个靶点具有主要抑制活性的母体化合物或支架中的策略，以开发一种小分子，该小分子可抑制两个或三个分子努力提高对抗多因素疾病的效力的目标。我们还讨论了美国食品和药物管理局 (FDA) 批准的多激酶抑制剂 (MKI) 的构效关系 (SAR)、理化性质、多药理学、支架特征提取的分析探索，以及双靶点临床状态的更新化学型。