HALOPHORE · Development of Reporter Tools for an Improved Understanding of Pharmacophore–Protein–Interaction
FP7 — People (Marie Curie Actions)
- Duration
- 2012-04-15 → 2014-04-14
- EU contribution
- €174,017
- Participants
- 1
- Scheme
- MC-IEF
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Results in brief
Development of Reporter Tools for an Improved Understanding of Pharmacophore–Protein–Interaction
Approximately 50% of the compounds in present high throughput drug screens are halogenated, yet the role of the halogens in their bioactivity has not yet been elucidated. Halogen bonding has been proposed to have a potential to become a future tool for increased activity and selectivity of pharmaceutics. It is an electron density donation-based weak interaction that has so far almost exclusively been investigated in computational and crystallographic studies. It shows high similarities to hydrogen bonding; however, its applicability for molecular recognition processes long remained unappreciated and has not been thoroughly explored. The main goals of this project are to develop halogenated reporter compounds and use them to achieve the first systematic description of halogen bonding in solution. These studies are expected to provide the basis of future applications of halogen bonding in solutions. Throughout the project halogenated, paramagnetic reporter compounds were prepared using solution-phase organic synthesis.
Data: CORDIS, © European Union
Project objective
Halogen bonding is an electron density donation-based weak interaction that has so far almost exclusively been investigated in computational and crystallographic studies. It shows high similaritiesto hydrogen bonding; however, its applicability for molecular recognition processes long remained unappreciated and has not been thoroughly explored.The main goals of this project are (1) to develop halogenated reporter compounds, using these (2) to perform the first ever systematic physicochemical study of halogen bonding in solutions, and (3) to apply the gained knowledge in structural biology through elucidation of the pharmacophore binding site of native proteins.Halogenated, paramagnetic, organometallic reporter compounds will be prepared using solution-phase organic synthesis. They will first be studied on small, well-designed organic model systems providing halogen bond donor and acceptor sites, mimicking those involved in the binding of pharmacophores to proteins and subsequently be used to investigate weak, protein-ligand interactions.The role of the participating halogen atom, the nature of the electron donors (N, O, S; n- and p-donors) and the influence of the environment (i.e. solvent) on the interaction, will be investigated. In this process NMR techniques will utilize paramagnetic effects and permit simultaneous characterization of bond strength and geometry of weak intermolecular complexes. It will be exploited to gain an atomic level understanding of anaesthesia with proteins involved in cellular calcium regulation. This in turn is of direct clinical relevance by providing a long-sought understanding of the disease malignant hyperthermia.In the proposed project I wish to combine my knowledge in chemistry, organometallic and physical chemistry to provide new theoretical insights in molecular recognition processes, to apply these for the understanding of pharmacophore–protein–Interaction and thereby give the basis for advances in drug developent.""
Original text from CORDIS.
Participants
- GOETEBORGS UNIVERSITET · GoeteborgCoordinatorSweden
Links
Data: CORDIS, © European Union