Chamelogk: A Chromatographic Chameleonicity Quantifier to Design Orally Bioavailable Beyond-Rule-of‑5 Drugs

New chemical modalities in drug discovery include molecules belonging to the bRo5 chemical space. Because of their complex and flexible structure, bRo5 compounds often suffer from a poor solubility/permeability profile. Chameleonicity describes the capacity of a molecule to adapt to the environment through conformational changes; the design of molecular chameleons is a medicinal chemistry strategy simultaneously optimizing solubility and permeability. A default method to quantify chameleonicity in early drug discovery is still missing. Here we introduce Chamelogk, an automated, fast, and cheap chromatographic descriptor of chameleonicity. Moreover, we report measurements for 55 Ro5 and bRo5 compounds and validate our method with literature data. Then, selected case studies (macrocycles, nonmacrocyclic compounds, and PROTACs) are used to illustrate the application of Chamelogk in combination with lipophilicity (BRlogD) and polarity (Δ log kwIAM) descriptors. Overall, we show how Chamelogk deserves being included in property-based drug discovery strategies to design oral bioavailable bRo5 compounds.药物研发中的新型化学模态涵盖了属于超出类药五规则（beyond Rule of 5, bRo5）化学空间的分子。由于结构复杂且柔性较强，bRo5化合物通常存在溶解度与透过性不佳的问题。构象变色龙性（chameleonicity）指分子通过构象变化适应环境的能力；分子变色龙设计是一种可同时优化溶解度与透过性的药物化学策略。目前在药物研发早期阶段，仍缺乏可量化构象变色龙性的通用方法。本研究提出了Chamelogk——一种可量化构象变色龙性的自动化、快速且低成本的色谱描述符。此外，本研究测定了55个符合类药五规则（Rule of 5, Ro5）与bRo5的化合物，并利用已发表文献数据对该方法进行了验证。随后，本研究选取大环化合物、非大环化合物以及蛋白降解靶向嵌合体（PROTACs）作为案例研究对象，阐明了Chamelogk与亲脂性描述符BRlogD、极性描述符ΔlogkwIAM联合使用的应用场景。综上，本研究证实Chamelogk可被纳入基于性质的药物研发策略，用于设计具备口服生物利用度的bRo5化合物。