Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs. Both cell permeability and aqueous solubility are required for the oral absorption of drugs. Engineering these properties, and potent target binding, into the larger new modalities is a more daunting task than for traditional small-molecule drugs. The ability of chameleons to adapt to different environments may be essential for success. In this Review, we provide both general and theoretical insights into the realm of molecular chameleons. We discuss why chameleons have come into fashion and provide a do-it-yourself toolbox for their design; we then provide a glimpse of how advanced in silico methods can support molecular chameleon design.

分子变色龙具有灵活性，使它们能够根据环境特性动态屏蔽或暴露极性功能。尽管分子变色龙的概念早在 1970 年就已被引入，但自 2010 年代以来，人们对它们的兴趣大大增加，当时药物发现越来越多地集中在新的化学模式上。这些模式包括环肽、大环化合物和蛋白水解靶向嵌合体，所有这些都存在于远离传统小分子药物的化学空间中。药物的口服吸收需要细胞渗透性和水溶性。将这些特性和有效的靶点结合设计成更大的新模式是比传统小分子药物更艰巨的任务。变色龙适应不同环境的能力可能对于成功至关重要。在这篇综述中，我们提供了对分子变色龙领域的一般和理论见解。我们讨论为什么变色龙会流行起来，并为它们的设计提供一个DIY工具箱；然后我们将介绍先进的计算机方法如何支持分子变色龙设计。