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Toward Physics-Based Solubility Computation for Pharmaceuticals to Rival Informatics

Fowles, DJ; Palmer, DS; Guo, R; Price, SL; Mitchell, JBO; (2021) Toward Physics-Based Solubility Computation for Pharmaceuticals to Rival Informatics. Journal of Chemical Theory and Computation 10.1021/acs.jctc.1c00130. (In press). Green open access

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Abstract

We demonstrate that physics-based calculations of intrinsic aqueous solubility can rival cheminformatics-based machine learning predictions. A proof-of-concept was developed for a physics-based approach via a sublimation thermodynamic cycle, building upon previous work that relied upon several thermodynamic approximations, notably the 2RT approximation, and limited conformational sampling. Here, we apply improvements to our sublimation free-energy model with the use of crystal phonon mode calculations to capture the contributions of the vibrational modes of the crystal. Including these improvements with lattice energies computed using the model-potential-based Ψmol method leads to accurate estimates of sublimation free energy. Combining these with hydration free energies obtained from either molecular dynamics free-energy perturbation simulations or density functional theory calculations, solubilities comparable to both experiment and informatics predictions are obtained. The application to coronene, succinic acid, and the pharmaceutical desloratadine shows how the methods must be adapted for the adoption of different conformations in different phases. The approach has the flexibility to extend to applications that cannot be covered by informatics methods.

Type: Article
Title: Toward Physics-Based Solubility Computation for Pharmaceuticals to Rival Informatics
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jctc.1c00130
Publisher version: http://doi.org/10.1021/acs.jctc.1c00130
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery-pp.ucl.ac.uk/id/eprint/10128630
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