The Front Cover illustrates neutral TPSA as a novel design principle in bRo5 space. Neutral TPSA is polarity that doesn′t translate into polar surface area. The plot shows the evolution of neutral TPSA in the lead optimisation of three first-in-class de novo designed oral bRo5 drugs, illustrated with the sigma density colored surface representations of fragment hits and venetoclax in the single molecule X-ray (CCDC AQUPEK) and co-crystal conformation (PDB 6o0l). Initially postulated as a descriptor of chameleonicity (i.e., environment-dependent change of conformation and polarity), this paper shows that neutral TPSA occurs independent of conformation, intramolecular hydrogen bonds (IMHB), and size, suggesting it is an intrinsic molecular property. More information can be found in the Research Article by Henrik Möbitz.

中文翻译：

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封面：超越 5 规则空间中平衡亲脂性和渗透性的设计原则 (ChemMedChem 5/2024)

封面展示了中性 TPSA 作为 bRo5 空间中的新颖设计原则。中性 TPSA 是极性，不会转化为极性表面积。该图显示了中性 TPSA 在三种一流的从头设计的口服 bRo5 药物的先导物优化中的演变，并以单分子 X 射线 (CCDC AQUPEK) 中片段命中和 Venetoclax 的西格玛密度彩色表面表示进行说明和共晶构象（PDB 6o0l）。本文最初被假定为变色性（即构象和极性的环境依赖性变化）的描述符，表明中性 TPSA 的发生独立于构象、分子内氢键 (IMHB) 和大小，表明它是一种内在的分子特性。更多信息请参阅 Henrik Möbitz 的研究文章。