Novel Descriptors and Models for More Accurate ADME and PK Predictions of Beyond Rule of Five Molecules

Authors: Jones J, Bachorz RA, Chupakhin V, Lawless M, Miller D, Fraczkiewicz R
Conference: DDC
Keywords: admet predictor, beyond rule-of-five, drug discovery, high throughput PK (HTPK), htpk simulation, PK predictions
Software: ADMET Predictor®

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 EPSA1, ChromLogD2, and ChameLogK3 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 (PK) endpoints, 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 this challenging chemical space.

By Jeremy O. Jones, Rafał A. Bachorz, Vladimir Chupakhin, Michael Lawless, David Miller, and Robert Fraczkiewicz

CHI Drug Discovery Chemistry, April 13th – 16th, 2026, San Diego, CA