Exploring the CSD Drug Subset: An Analysis of Lattice Energies and Constituent Intermolecular Interactions for the Crystal Structures of Pharmaceuticals.
| Autor: | Ma CY; Centre for the Digital Design of Drug Products, School of Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK. Electronic address: c.y.ma@leeds.ac.uk., Moldovan AA; The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK., Maloney AGP; The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK., Roberts KJ; Centre for the Digital Design of Drug Products, School of Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Journal of pharmaceutical sciences [J Pharm Sci] 2023 Feb; Vol. 112 (2), pp. 435-445. Date of Electronic Publication: 2022 Dec 01. |
| DOI: | 10.1016/j.xphs.2022.11.027 |
| Abstrakt: | Intermolecular (synthonic) modelling is used for a statistical analysis of crystal lattice energies, together with their contributing intermolecular interactions for the crystallographic structures selected from the CCDC's Drug Subset (https://doi.org/10.1016/j.xphs.2018.12.011). Analysis of this selected subset reveal similarities in packing compared to other organic crystals in the CSD with linear relationships between molecular weight and unit cell volume, void space, and packing coefficient. Crystal lattice energy calculations converge within a 30 Å intermolecular radius characterised by a mean lattice energy of ca. -36 kcal mol -1 with ca. 85% and 15% due to dispersive and electrostatic interactions, respectively. The distribution of the strongest synthons within the individual structures reveals an average strength of -5.79 kcal mol -1 . The diversity of chemical space within the drug molecules is in agreement with the analysis of atom types across the selected subset with phenyl groups being found to contribute the highest mean energy of -11.28 kcal mol -1 , highlighting the importance of aromatic interactions within pharmaceutical compounds. Despite an initial focus on Z' = 1 structures, this automated approach enables rapid and consistent quantitative analysis of lattice energy, synthon strength and functional group contributions, providing solid-form informatics for pharmaceutical R&D and a helpful basis for further investigations. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|