Biochemical and Chemical Methods to Stabilize Transient Binding Pockets

Due to their elusive character, transient binding pockets need to be stabilized for proper investigation. Therefore, four different chemical approaches are tested, to facilitate chemical stability of transient binding pockets which enhances their longevity making them far better observable.

C1 Kolmar: Protein Engineering

Proteins to be investigated within TRABITA are found in an equilibrium between transient binding pockets and their native conformation. Prior to this project, Prof. Kolmar's work group has successfully used engineered antibodies to isolate testing mutants of FKBP51, which feature a stabler transient binding pocket. This applied methodology will be enhanced and tailored to the other protein models within TRABITA.

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C2 Schmitz: Particle-Based Libraries

Transient binding pocket instability can be mitigated by regulatory peptides. Influencing this conformational equilibrium has already been achieved and is shown in publications about HDAC and 5-LO. Prof. Schmitz' and her coworkers' goal is to stabilize some protein models of TRABITA. They will utilize peptide and peptoide libraries, likewise to those developed for chemokine binding partners in the past.

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C3 Proschak: Fragment Libraries

Molecular fragments can be used as ligands for TRABITA. The work group of Prof. Proschak generates and evaluates large fragment libraries. Machine Learning and other computational Methods will play an important role in finding suitable chemical structures. Afterwards, found structures will be evaluated by experiments.

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C4 Schmidt: Medicinal Chemistry

The workgroup of Prof. Schmidt focuses on covalent kinase inhibitors. One family of kinase proteins features a cystein in reaction site proximity which can be targeted to influence enzyme activity. One method to select new lead structures is to derivatize the cystein and simultaneously occupy the postulated transient binding pocket.

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