Molecular properties, including chameleonicity, as essential tools for designing the next generation of oral beyond rule of five drugs

Abstract

Background and Purpose. The classical drug discovery toolbox continually expands beyond traditional rule of five (Ro5)-compliant small molecules to include new chemical modalities for difficult-to-drug targets. The paper focuses on the molecular properties essential to drive oral bioavailability within the bRo5 framework. Experimental Approach. The first part outlines the concept and methodologies for characterizing bRo5 physicochemical properties, including considerations on chameleonicity; in particular, the paper sum­marizes the content of the last author’s talk presented during the IAPC-10 Meeting held in Belgrade in September 2023 (https://iapchem.org/index.php/iapc-10-home). The second part of the manuscript presents novel experimental and computational data on three proteolysis targeting chimeras (PROTACs) currently in clinical trials. Key Results. Molecular descriptors of ARV-110, ARV-471, and DT-2216 are reported and the main limitations of the applied experimental approaches are discussed. Moreover, a simple computational method shows how predicting the presence of chameleonic effects. Conclusion. A full complete physicochemical characterization of three degraders in clinical trial is reported to highlight the differences in physicochemical descriptors between PROTACs dosed orally and intravenously.

Keywords

• bRo5
• chameleonicity
• ionization
• lipophilicity
• new chemical modalities
• polarity