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A Quantum Chemical Deep-Dive into the π-π Interactions of 3-Methylindole and Its Halogenated Derivat


Researchers from the General Chemistry Group (ALGC) and the Organic Chemistry Research Group (ORGC) at the Vrije Universiteit Brussels (VUB) recently published an article on 3-methylindole-derived molecules in the journal Pharmaceuticals. In their work, they explore the subtle stacking interactions that make these molecules interesting in the context of drug development and protein stability. Only through leveraging expensive quantum theory calculations, for which the resources provided by the VSC are indispensable, could highly accurate insights be obtained that help the field make rational design decisions for new indole-based small-molecule drugs.




π-π stacking interactions are ubiquitous in nature and biological chemistry. A better fundamental understanding of the factors that determine the stability of these interactions can lead to new strategies for the synthetic development of molecules whose applications rely on π-π stacking. Indole-derived molecules, a common motif found in pharmaceutical drugs, is one example of such a molecule. Substituting atoms on the indole molecules is expected to influence the strength and nature of the stacking interactions, but the exact fundaments behind this remain elusive.


Figure 1. Calculated interaction energies allows the assessment of the stability of (A) mono- and (B) dihalogenated 3-methylindole stacked dimers.


The groups of Prof. Frank De Proft and Prof. Steven Ballet at the Vrije Universiteit Brussels joined forces to fill this knowledge gap and provide the field with an elaborate quantum chemical investigation on how substitution affects the stacking stability of 3-methylindole. The results revealed that placing a halogen atom on the 3-methylindole ring can both decrease and increase the stacking stability, depending on the pattern of substitution as well as the type of halogen atom. Moreover, based on the data collected from these resource-intensive quantum chemical calculations, the researchers deduced a practical model, that will allow others to more easily assess and quantify the stacking stability of similar molecules.

Only through leveraging expensive quantum theory calculations, for which the resources provided by the VSC are indispensable, could highly accurate insights be obtained that help the field make rational design decisions for new indole-based small-molecule drugs.

The sheer amount of computationally intensive calculations performed, made the facilities provided by both the VSC and VUB crucial for the tractability and successful completion of this project. In addition, the researchers harnessed the full potential of the computed data, by deriving a simplified model that makes the research accessible to scientists that do not enjoy the luxury of a powerful computing cluster.


More information and the full publication can be found at https://doi.org/10.3390/ph15080935

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