A Free Energy Perturbation Approach to Estimate the Intrinsic Solubilities of Drug-like Small Molecules

Abstract

<p>Optimizing the solubility of small molecules is important in a wide variety of contexts, including in drug discovery where the optimization of aqueous solubility is often crucial to achieve oral bioavailability. In such a context, solubility optimization cannot be successfully pursued by indiscriminate increases in polarity, which would likely reduce permeability and potency. Moreover, increasing polarity may not even improve solubility itself in many cases, if it stabilizes the solid-state form. Here we present a novel physics-based approach to predict the solubility of small molecules, that takes into account three-dimensional solid-state characteristics in addition to polarity. The calculated solubilities are in good agreement with experimental solubilities taken both from the literature as well as from several active pharmaceutical discovery projects. This computational approach enables strategies to optimize solubility by disrupting the three-dimensional solid-state packing of novel chemical matter, illustrated here for an active medicinal chemistry campaign.</p>

Best Practices for Alchemical Free Energy Calculations [Article v1.0]

“…From a drug discovery point of view, alchemical calculations are expanding their domain of applicability, and there are reports of success using homology models [99] and GPCRs [100,101] for instance, as well as enabling charge change and scaffold hopping [102,103], but these systems are undoubtedly more difficult. In the meantime, the use cases are expanding to resistance prediction, selectivity prediction , solubility prediction -an exciting future for alchemical calculations [6,104,105].…”

Three machine learning models for the 2019 Solubility Challenge

“…Finally, it is hoped that some of the various first principles methods under development [5][6][7][8][9][10][11] are in due course tested on Avdeef's datasets, or on similar reasonably sized sets. As yet, most have been validated on only a handful of compounds.…”

“…Solubility is also a significant challenge for computational chemistry [3,4]. First principles approaches have made some progress in recent years, and in the longer term may provide the most satisfactory means of computing solubility [5][6][7][8][9][10][11]. However, currently such first principles methods require a substantial amount of computer time and, despite potentially providing more theoretical insight, are generally less accurate in their quantitative predictions [3] than are the more empirical informatics approaches.…”

Best Practices for Alchemical Free Energy Calculations

“…From a drug discovery point of view, alchemical calculations are expanding their domain of applicability, and there are reports of success using homology models [89] and GPCRs [90,91] for instance, as well as enabling charge change and scaffold hopping [92,93], but these systems are undoubtedly more difficult. In the meantime, the use cases are expanding to resistance prediction, selectivity prediction , solubility prediction -an exciting future for alchemical calculations [6,94,95].…”