Research projects in Erdélyi Group
We investigate fundamental concepts of chemical bonding, molecular structure and reactivity with focus on biological systems, biomolecules and natural products. We are particularly strong in the NMR area, where we work a lot with method development. The aim of our research is to identify substances with potential medical efficacy and to develop methods that can facilitate and streamline drug development.
Halogen bonding in solution
Halogen bonding is an electron density donation-based weak interaction that has so far mostly been investigated in computational and crystallographic studies. We examine halogen bonds formed in solution using exceedingly accurate NMR methodologies. By combining spectroscopic and computational techniques, we describe the energetics of halogen bonds and the impact of electrostatic and non-electrostatic effects in the formation of the interaction. Variation of bond length and symmetry as well as their relevance in inter- and intramolecular interactions are also being elucidated.
The gained knowledge will be applied to understand the impact of halogen bonding in biological systems, such as protein-ligand and lipid-ligand interactions as well as used to develop new applications of halogen bonding in organic, analytical and pharmaceutical chemistry. We have pioneered the field of three-centre halogen bonds and have described the influence of the identity of the halogen, the polarity of the solvent, the electronic effects of substituents, and geometric factors, for example, on the interaction. We also study the applicability of halogen bonding in medicinal chemistry and structural biology, and have demonstrated that a halogen bonds can stabilize a peptide foldamer to the same extent as for example a hydrogen bond.
Natural products
Malaria, caused by the protozoan parasites of the genus Plasmodium, is a major disease in the tropical and subtropical regions of the world. Out of yearly 300 to 500 million clinical episodes, of which 90% occur in tropical sub-Saharan region, 1.5-2.7 million are lethal. Notably, malaria is the leading cause of mortality of children under five years of age and of pregnant women in this area.
The emergence of chloroquine-resistant strains of the parasite Plasmodium falciparum and the rising resistance of the vectors (Anopheles spp.) to insecticides in combination with poverty and lack of a well-functioning health care system are the main causes for the increase of malaria morbidity and mortality over the past decade. To date over thousand herbal species are in use in indigenous health systems as means of treating malaria and managing related fever; however, their efficacy and active components have not yet been studied systematically. Although there are several antimalarial drugs on the market, most do not meet the requirement of ≤ 1 USD per treatment and are unaffordable for the majority of Africa. Chloroquine and sulphadoxine-pyrimethamine are the only remedy available for such low price; however, the already widespread and relentlessly increasing resistance against these agents makes them virtually useless. The discovery of Artemisinin from Artemisia annua has shown that plants used in traditional medicine may provide new source of lead structures for the development of novel antiplasmodial drugs.
The goal of this ongoing project is identification of novel pharmaceutical lead compounds from the Kenyan flora by evaluation of efficacious traditional remedies by modern techniques. We collaborate with the research group of Prof. Abiy Yenesew at the University of Nairobi, Kenya, and aim to join our forces by integrating cultural practice with modern pharmaceutical approaches to advance new solutions to malaria. Expected outcomes of the project are bioactive natural products rapidly transferable to the treatment of malaria - either through identification of new lead compounds or through development of phytomedicines.
Paramagnetic ligand tagging technology
Access to 3D-structural information on the protein complexes of pharmaceutical screening hits is necessary for their development into lead molecules, i.e. starting points for new drugs. Due to inefficiency – and often inability – of current spectroscopic and crystallisation methods to provide detailed structural information of low affinity hit-target complexes, this step is a major bottleneck of modern drug development.
We are establishing a novel concept for the determination of the binding site and binding mode of bioactive substances to their target proteins in solution. We synthesise paramagnetic tags that can be attached to virtually any types of substances, and that provide structural information with at least hundred times higher sensitivity than conventional techniques. This new technique increases the efficiency of drug development, by making it cheaper and faster, and enable development of hits otherwise discarded.
We have used this technique to identify the binding calmodulin binding sites of the anesthetic agent sevoflurane. This is especially difficult as sevoflurane is volatile, has low aqueous solubility and low binding affinity making crystallization practically impossible. This work is described in J. Am. Chem. Soc. 2015, 137, 11391.