A Quantum Chemical Deep-Dive into the π-π Interactions of 3-Methylindole and Its Halogenated Derivatives—Towards an Improved Ligand Design and Tryptophan Stacking

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Abstract

Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally accepted that minor structural changes to the aromatic ring, such as substitution, can have a large influence on these interactions. Nevertheless, a thorough understanding of underpinning phenomena guiding these key interactions is still limited. This is especially true for larger aromatic structures. To expand upon this knowledge, elaborate ab initio calculations were performed to investigate the effect of halogenation on the stability of 3-methylindole stacking. 3-Methylindole served as a representation of the tryptophan side chain, and is a frequently used motif in drug design and development. Moreover, an expression is derived that is able to accurately predict the interaction stability of stacked halogenated 3-methylindole dimers as well as halogenated toluene dimers, based on monomer level calculated DFT descriptors. We aim for this expression to provide the field with a straightforward and reliable method to assess the effect of halogenation on the π-π stacking interactions between aromatic scaffolds.

Original languageEnglish
Article number935
Number of pages13
JournalPharmaceuticals
Volume15
Issue number8
DOIs
Publication statusPublished - Aug 2022

Bibliographical note

Funding Information:
This research was funded by FWO, grant number 1185221N and the Research Council of the VUB (SRP50) and the Flemish Government’s Industrial Research Fund (IOF).

Funding Information:
R.V.L. and T.B. acknowledges the use of Tier2 computational resources and services provided by the Shared ICT Services Centre funded by the Vrije Universiteit Brussel, the Flemish Supercomputer Center (VSC), and FWO. R.V.L. thanks FWO for the Ph.D. fellowships received (1185221N). F.D.P. wishes to acknowledge the Vrije Universiteit Brussel for the support through a Strategic Research Program. J.B., T.M.A.B. and S.B. acknowledge the financial support of the Research Foundation Flanders (FWO), the Research Council of the VUB (through the Strategic Research Program SRP50) and the Flemish Government’s Industrial Research Fund (IOF).

Publisher Copyright:
© 2022 by the authors.

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

Keywords

  • pi-pi stacking
  • peptides
  • density functional theory
  • indoles
  • non-covalent interactions

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