Abstract

This study addresses the critical need for improved physicochemical descriptors and predictive models tailored to beyond Rule of Five (bRo5) compounds, including PROTACs and cyclic peptides. By integrating experimental parameters such as EPSA, ChromLogD, and ChameLogK with computationally derived features of molecular chameleonicity, we aim to establish new structure-property relationships that better capture the dynamic polarity and conformational adaptability of these complex molecules. The resulting models are designed to enhance the prediction of key in vitro ADME and in vivo pharmacokinetic endpoints such as passive permeability, solubility, fraction unbound in plasma, and fraction absorbed, ultimately providing a more reliable framework for the design and optimization of developable bRo5 therapeutics. Case studies demonstrate the contribution of these new descriptors to model building as well as improvements in predicting key in vivo endpoints for challenging chemical space, supporting modern drug discovery.

By Jeremy O Jones, Robert Fraczkiewicz, Rafal A Bachorz, Vladimir Chupakhin, Michael Lawless, David Miller, Viera Lukacova