Project I - Computer-aided rational design of compounds for imaging transporters

The aim of this project is to use theoretical chemistry to optimize the absorption and emission properties of fluorescent compounds that will be used as molecular tools for imaging of various neurotransmitter transporters such as dopamine transporter and organic cation transporters 3. In order to understand the luminescence properties of novel fluorescent dyes, stationary quantum chemical calculations of the electronic excited states will be performed. Furthermore, ab initio molecular dynamics methods will be used to predict possible non-adiabatic competing deactivation pathways and help the best possible functionalization of the compounds.

Networking: This project will be done in cooperation with the group of Maulide, where the fluorescent dyes will be synthetized and functionalized according to the theoretical predictions, and the group of Sitte, where the optimized fluorophore will be attached to molecules such as Corticosterone for imaging neurotransmitter transporters.

Project II - In silicon design of photo switchable allosteric modulators for GABA_A receptors

The vast structural and functional know-how gained in the last years in MolTag on γ-Aminobutyric acid type A (GABA_A) receptors opens up a unique opportunity to design selective GABA_A photoswitchable allosteric modulators with fine-tune subtype selectivity. On the one side, most therapeutics that target these receptors do not act at the agonist (GABA) sites, but rather as allosteric modulators that enhance or diminish GABA elicited channel opening or change desensitization kinetics. On the other side, the introduction of photoswitchable/photoreactive moieties into these allosteric modulators can provide optopharmacological tools to understand better the physiological and pathological role of individual subtypes of the large family of GABA_A receptors. In this project, novel soluble photochromic ligands e.g. based on the positive allosteric propofol, will be simulated with the aim to introduce some subtype selectivity using state-of-art theoretical tools. To this aim, photo-switching mechanisms will be investigated using quantum chemical and dynamical calculations. Importantly, the interactions with biological environments will be taken into account in our computations using multiscale hybrid quantum mechanics/molecular mechanics methods (QM/MM).

Networking: The Ernst lab will provide several candidate compounds based on computational docking studies done jointly with the Ecker group. Structural models of the GABA_A receptors will be obtained from structural databases and refined by modelling via potential collaboration with the Weinzinger lab. The function of the original and modified photoswitch candidates will be investigated in the Ernst lab. The photoswitchable allosteric modulators will be synthetized in the group of Mihovilovic.