Front Cover: Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space (ChemMedChem 5/2024) (ChemMedChem 5/2024)
Henrik Möbitz · ChemMedChem · 2024
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.