It is well known that small molecule colloidal aggregation is a leading cause of false positives in early drug discovery. Colloid-formers are diverse and well represented among corporate and academic screening decks, and even among approved drugs. Less appreciated is how colloid formation by drug-like compounds fits into the wider understanding of colloid physical chemistry. Here we introduce the impact that colloidal aggregation has had on early drug discovery, and then turn to the physical and thermodynamic driving forces for small molecule colloidal aggregation, including the particulate nature of the colloids, their critical aggregation concentration-governed formation, their mechanism of protein adsorption and subsequent inhibition, and their sensitivity to detergent. We describe methods that have been used extensively to both identify aggregate-formers and to study and control their physical chemistry. While colloidal aggregation is widely recognized as a problem in early drug discovery, we highlight the opportunities for exploiting this phenomenon in biological milieus and for drug formulation.

中文翻译：

---

胶体聚集：从筛选问题到配方细微差别

众所周知，小分子胶体聚集是早期药物发现中假阳性的主要原因。胶体形成剂是多种多样的，并且在企业和学术筛选平台中，甚至在批准的药物中都有很好的代表性。较少理解的是，药物样化合物的胶体形成如何符合对胶体物理化学的更广泛理解。在这里，我们介绍了胶体聚集对早期药物发现的影响，然后转向小分子胶体聚集的物理和热力学驱动力，包括胶体的颗粒性质、它们的临界聚集浓度控制形成、它们的作用机制。蛋白质吸附和随后的抑制，以及它们对洗涤剂的敏感性。我们描述了已广泛用于识别聚集体形成者以及研究和控制其物理化学的方法。虽然胶体聚集被广泛认为是早期药物发现中的一个问题，但我们强调了在生物环境和药物配方中利用这种现象的机会。