From drug discovery to drug development: The role of intermolecular interactions in drug solid forms

Cvetkovski, Aleksandar (2023) From drug discovery to drug development: The role of intermolecular interactions in drug solid forms. In: Novel leads and drugs and their mechanism of action in the field of vector borne parasitic disease, 15 May 2023, online. (Unpublished)

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Abstract

All available strategies for drug discovery, both the searching the known receptor/enzyme structures and testing the metabolic paths for the unique molecular structures of the new synthetized or isolated compounds are relied on intermolecular recognition on the binding sites. Crystal engineering, on the other hand, utilizes the inherent structural moieties “synthons” formed by spatial interactions that nature and geometry depend on the type of the functional groups and/or molecular structures leading to their reproducibility during the molecules/ions pack each other during the macroscopic crystal growth. Therefore, analysis of around 138 000 small-molecule structures deposited in the Cambridge Structural Database (CSD) offer opportunities for statistical assessment of the propensity of occurring different type of synthons in different classes of chemical compounds which molecular structures are packed in crystallographic classes of monocomponent or multicomponent single phases of crystals. In order to screen the specific binding compatibility with the protein targets, extrapolation of the synthons in the CSD, that describes the shape and interaction propensities of molecules in their crystal structures, enables to optimize the high-throughput screening new leading compounds for their favorable drug–protein crystal structures. In addition, electron-density-based intermolecular boundary surfaces in small-molecule crystal structures and in target-protein binding sites are tool to identify potential ligand molecules from the CSD based on 3D shape and intermolecular interaction matching [1].
Crystal engineering concept becomes crosscut stage where overlapping drug discovery and drug development enable tailoring the desirable properties through screening the solid phases and selection the appropriate one. The nature of non-covalent interactions among molecular/ionic counterparts in stoichiometric ratio influence either crystallization of the single component solids (polymorphs) or multicomponent solids (solvates/hydrates, salts, cocrystals or inclusion complexes etc.) to occur beside the amorphous solid phases [2].
The presented case studies for searched crystal structures for several compound classes of antiparasitic drugs which are deposited in Cambridge Structural Database (https://www.ccdc.cam.ac.uk/) reveal the opportunities for studying the frequency, prevalence and hierarchy of appearing the non-covalent interactions in their molecular crystals and to perceive the opportunities for designing new solid phases for multicomponent crystals of either the combinations of antiparasitic drugs with different molecular structures or antiparasitic drug cocrystalized with reliable conformer that improve the drug properties.

References
[1] P. R. Spackman, L.-J. Yu, C. J. Morton, M. W. Parker, C. S. Bond, M. A. Spackman, D. Jayatilaka, S. P. Thomas, Angew. Chem. Int. Ed. 2019, 58, 16780..
[2] S. Aitipamula, et al., Crystal Growth & Design (2012) 12 (5), 2147-2152

Item Type:	Conference or Workshop Item (Lecture)
Subjects:	Medical and Health Sciences > Basic medicine Engineering and Technology > Chemical engineering Natural sciences > Chemical sciences Engineering and Technology > Nano-technology
Divisions:	Faculty of Medical Science
Depositing User:	Aleksandar Cvetkovski
Date Deposited:	17 May 2023 08:56
Last Modified:	17 May 2023 08:56
URI:	https://eprints.ugd.edu.mk/id/eprint/31765

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