Beyond Rule of Five and PROTACs in Modern Drug Discovery: Polarity Reducers, Chameleonicity, and the Evolving Physicochemical Landscape

Developing orally bioavailable drugs demands an understanding
of
absorption in early drug development. Traditional methods and physicochemical
properties optimize absorption for rule of five (Ro5) compounds; beyond
rule of five (bRo5) drugs necessitate advanced tools like the experimental
measure of exposed polarity (EPSA) and the AbbVie multiparametric
score (AB-MPS). Analyzing AB-MPS and EPSA against ∼1000 compounds
with human absorption data and ∼10,000 AbbVie tool compounds
(∼1000 proteolysis targeting chimeras or PROTACs, ∼7000
Ro5s, and ∼2000 bRo5s) revealed new patterns of physicochemical
trends. We introduced a high-throughput “polarity reduction”
descriptor: ETR, the EPSA-to-topological polar surface area (TPSA)
ratio, highlights unique bRo5 and PROTAC subsets for specialized drug
design strategies for effective absorption. Our methods and guidelines
refine drug design by providing innovative in vitro approaches, enhancing
physicochemical property optimization, and enabling accurate predictions
of intestinal absorption in the complex bRo5 domain.