Show simple item record

Files in this item


Item metadata

dc.contributor.authorFowles, Daniel J.
dc.contributor.authorPalmer, David S.
dc.contributor.authorGuo, Rui
dc.contributor.authorPrice, Sarah L.
dc.contributor.authorMitchell, John B. O.
dc.identifier.citationFowles , D J , Palmer , D S , Guo , R , Price , S L & Mitchell , J B O 2021 , ' Toward physics-based solubility computation for pharmaceuticals to rival informatics ' , Journal of Chemical Theory and Computation , vol. 17 , no. 6 , pp. 3700-3709 .
dc.identifier.otherPURE: 274343482
dc.identifier.otherPURE UUID: 118e9be9-105c-49a2-8c24-3cdabe7e8f94
dc.identifier.otherJisc: 3a1140f9a97f4314a0f78347ab537b12
dc.identifier.otherORCID: /0000-0002-0379-6097/work/94669110
dc.identifier.otherScopus: 85106459352
dc.identifier.otherWOS: 000661542700037
dc.descriptionD.S.P. and D.J.F. thank the EPSRC for funding via Prosperity Partnership EP/S035990/1. D.S.P. and D.J.F. thank the ARCHIE-WeSt High-Performance Computing Centre ( for computational resources. The UCL authors thank Prof. Keith Refson for guidance with the phonon calculations, which used the ARCHER U.K. National Supercomputing Service ( as part of the U.K. HEC Materials Chemistry Consortium, which is funded by the EPSRC (EP/L000202, EP/R029431). R.G. was funded by MagnaPharm, a project funded by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement number 736899.en
dc.description.abstractWe 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.
dc.relation.ispartofJournal of Chemical Theory and Computationen
dc.rightsCopyright © 2021 The Authors. Published by American Chemical Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en
dc.subjectQD Chemistryen
dc.titleToward physics-based solubility computation for pharmaceuticals to rival informaticsen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

This item appears in the following Collection(s)

Show simple item record