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Ligand Development

Below the main research areas of our group in the field of ligand development.

Parkinson's Disease and Alzheimer's Disease

Parkinson's Disease (PD) is a fatal neurodegenerative disease, affecting about 1% of the population over the age of 65. Our Institute is investigating several molecular-level processes in PD, in collaboration with a variety of experimental labs:

A) α-synuclein and regulators of addregation

In a joint study by University Medical Center Göttingen, the Max Planck Institute for Biophysical Chemistry, the IIDEFAR institute in Rosario, Argentina, and INM-9, we were able to gain new insights into the functioning of alpha-synuclein, the protein that forms the major component for of the Lewy bodies in Parkinson’s. Specifically, we discovered interactions with environmental factors that contribute to an aggregation of α-synuclein [1,2].

H50Figure 1 - H50 residue is key for anchoring Cu2+ binding to alpha-synuclein. Quantum Mechanics / Molecular Mechanics (QM/MM) simulations were carried out to test the stability of all the possible coordination geometries of Cu2+ at H50 site, fitting available experimental evidences.


[1] A. Villar-Piqué et al., "Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity. PNAS 113(42), E6506-E6515 (2016).

[2] Press release: Umwelt trifft auf Genetik: Neue Erkenntnisse über die Parkinson-Krankheit

B) Human adenosine receptor and caffeine

In collaboration with Prof. Bauer (INM-2), we studied the human adenosine receptor type 2A (hA2AR) in complex with caffeine and other antagonist within different membrane types and with both biased and unbiased molecular dynamics smulation. Our calculations show that cholesterol presence, often neglected in X-ray studies  of membrane proteins, affects the population of the ligand binding poses. Including a correct description of neuronal membranes may be very important for computer-aided design of ligands targeting hA2AR and possibly other neuronal GPCRs. Our work further showed the fundamental role of loops for molecular recognition. This knowledge is currently beeing exploited to develop novel therapeutics and possibly diagnosis tools against PD.

ARFigure 2 - Adenosine receptor embedded in a neuronal-like membrane.

C) NEET proteins

mitoNEET and  NAF-1  are  homologous  proteins,  belonging  to  the  NEET  family.
These feature two intertwining monomers, each of which contains a labile 2Fe-2S cluster. Despite the functions of these proteins still need to be elucidated, experimental observations support the hypothesis that their function involves the gather/release of the FeS from/to holo-donor/apo-acceptor proteins. The lack of structural information for these proteins in absence of the iron-sulfur cluster(s) has so far hampered a molecular understanding of the key processes involving the cluster release. We are currently predicting the structural determinants of these proteins without one (holo-apo state) and two (apo-apo state) clusters in aqueous solution by Replica Exchange Solute Tempering (REST)2 enhanced simulations, driven by spectroscopic data.  This information is key for our planned future works aimed at finding molecular partners interfering with the cluster release. This project is in collaboration also with Prof. Nechushtai (Hebrew University, Israel).  It has been specifically funded by the FZJ (Vorstandsdoktoranden grant with Prof. Bauer (INM-2)).

Huntington's Disease

Huntington's disease is a neurodegenerative disorder producing motor, cognitive and psychiatric symptoms.
The gene responsible for the disease (HTT) encodes the ubiquitously expressed Huntingtin protein, which is essential for brain development. The disease is caused by an expanded CAG repeat in the 5′-end of the HTT mRNA. Huntington's disease penetrance is correlated to the number n of CAG repeats (the disease threshold is n=36) and HTT mRNA transcripts with n above threshold may contribute to the pathogenesis, aberrantly regulate several cellular mechanisms and bind to proteins to form pathological complexes.
Inhibiting the formation of such pathological protein/RNA complexes, targeting the expanded transcripts, may be a valuable strategy against the disease.
In our recent work, we used well-tempered metadynamics-based free energy calculations to investigate pose and affinity of two ligands targeting CAG repeats for which affinities have been previously measured. Our calculations reproduce the experimental affinities and uncover the recognition pattern between ligands’ and the RNA target. They also provide a molecular basis for the markedly different affinity of the two ligands for CAG repeats as observed experimentally.

HDFigure 3 - Free energy profiles (top) and binding poses (bottom) of the two ligands/CAG-RNA complexes. The calculated affinities, expressed in terms of the unbinding free energies (?Gs), are well in agreement with the experimental measurements (kds).

These findings pave the way for a structure-based hit-to-lead optimization to further improve ligand selectivity toward CAG repeats-containing mRNAs.
The work is in collaboration with Dr. Sybille Krauβ at the German Center for Neurodegenerative Diseases in Bonn and Prof. Oriana Tabarrini at the University of Perugia, in Italy.

Muscarinic receptor and allosteric ligands

Classical radiolabeled ligands were designed on the basis of their similarity with receptors’ substrates. The allosteric interaction paradigm, instead, provides the distinction between the orthosteric ligands (binding to the endogenous neurotransmitter sites as agonists or antagonists), and ligands that mediate their effects by interacting with topographically distinct allosteric sites on receptor. We are currently studying the adduct between the allosteric ligands and the muscarinic receptor M2 to rationalize the allosteric mechanisms of receptor modulation. Molecular simulations, combined with experimental characterization will help to design new radioligands with enhanced selectivity and thus reduced off-target effects.



MD simulation of Human Muscarinic receptor in complex with a positive allosteric modulator