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

preprint
submitted on 07.11.2019 and posted on 15.11.2019 by Sayan Mondal, Gary Tresadern, Jeremy Greenwood, Byungchan Kim, Joe Kaus, Matt Wirtala, Thomas Steinbrecher, Lingle Wang, Craig Masse, Ramy Farid, Robert Abel

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.

History

Email Address of Submitting Author

sayan.mondal@schrodinger.com

Institution

Schrödinger

Country

United States

ORCID For Submitting Author

0000-0002-1812-0575

Declaration of Conflict of Interest

No conflict of interest

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