Novel Physics-Based Ensemble Modeling Approach That Utilizes 3D Molecular Conformation and Packing to Access Aqueous Thermodynamic Solubility: A Case Study of Orally Available Bromodomain and Extraterminal Domain Inhibitor Lead Optimization Series

Drug design with
patient centricity for ease of administration
and pill burden requires robust understanding of the impact of chemical
modifications on relevant physicochemical properties early in lead
optimization. To this end, we have developed a physics-based ensemble
approach to predict aqueous thermodynamic crystalline solubility,
with a 2D chemical structure as the input. Predictions for the bromodomain
and extraterminal domain (BET) inhibitor series show very close match
(0.5 log unit) with measured thermodynamic solubility for cases with
low crystal anisotropy and good match (1 log unit) for high anisotropy
structures. The importance of thermodynamic solubility is clearly
demonstrated by up to a 4 log unit drop in solubility compared to
kinetic (amorphous) solubility in some cases and implications thereof,
for instance on human dose. We have also demonstrated that incorporating
predicted crystal structures in thermodynamic solubility prediction
is necessary to differentiate (up to 4 log unit) between solubility
of molecules within the series. Finally, our physics-based ensemble
approach provides valuable structural insights into the origins of
3-D conformational landscapes, crystal polymorphism, and anisotropy
that can be leveraged for both drug design and development.