Free Energy Perturbation Approach for Accurate Crystalline Aqueous Solubility Predictions.
J Med Chem
; 66(23): 15883-15893, 2023 12 14.
Article
em En
| MEDLINE
| ID: mdl-38016916
ABSTRACT
Early assessment of crystalline thermodynamic solubility continues to be elusive for drug discovery and development despite its critical importance, especially for the ever-increasing fraction of poorly soluble drug candidates. Here we present a detailed evaluation of a physics-based free energy perturbation (FEP+) approach for computing the thermodynamic aqueous solubility. The predictive power of this approach is assessed across diverse chemical spaces, spanning pharmaceutically relevant literature compounds and more complex AbbVie compounds. Our approach achieves predictive (RMSE = 0.86) and differentiating power (R2 = 0.69) and therefore provides notably improved correlations to experimental solubility compared to state-of-the-art machine learning approaches that utilize quantum mechanics-based descriptors. The importance of explicit considerations of crystalline packing in predicting solubility by the FEP+ approach is also highlighted in this study. Finally, we show how computed energetics, including hydration and sublimation free energies, can provide further insights into molecule design to feed the medicinal chemistry DMTA cycle.
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Base de dados:
MEDLINE
Assunto principal:
Água
/
Descoberta de Drogas
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article