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 the impact 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, 2D structure as input. Predictions bromodomain extraterminal domain (BET) inhibitor series show very close match (0.5 log unit) measured solubility cases low crystal anisotropy good (1 high structures. The importance is clearly demonstrated by up 4 unit drop compared kinetic (amorphous) some implications thereof, instance human dose. We also that incorporating predicted structures prediction necessary differentiate (up between molecules within series. Finally, our provides valuable structural insights into origins 3-D conformational landscapes, polymorphism, can be leveraged both drug development.