IMHB-Mediated Chameleonicity in Drug Design: A Focus on Structurally Related PROTACs

Molecular chameleonicity may enable compounds to compensate
for
the unfavorable ADME properties typically associated with complex
molecules, such as PROTACs. Here we present a few in silico strategies to implement chameleonicity considerations in drug design.
Initially, we identified six structurally related CRBN-based PROTACs
targeting BET proteins and experimentally verified whether chameleonicity
is needed to obtain an acceptable physicochemical profile. Then, we
utilized experimental data to validate our novel computational strategies
based on tools crafted to encompass a spectrum of complexities and
innovative features. After confirming that the formation of IMHBs
is the primary driving factor behind chameleonicity, we initially
utilized conformational sampling data to define cChameCS, an IMHB-mediated,
simple, and rapid chameleonicity predictor index suitable for early
drug discovery. Subsequently, we identified dynamic IMHB patterns
relevant to chameleonicity through molecular dynamics simulations.
Finally, we proposed a workflow for designing structurally related
chameleonic PROTACs of potential application in the lead optimization
process.