Speaker: Dr. Gergely Toth
Department of Chemistry, University of Cambridge, UK

Thursday, 9 September 2010, 9:30h, TORRE I - Sala 4 - 3rd Floor

ABSTRACT

In the seminar, I will present our efforts towards targeting two different protein systems, c-Jun N-terminal kinase 3 (JNK3) and α-synuclein, implicated as targets for Parkinson’s Disease (PD). In neurodegenerative diseases, the molecular mechanism of progressive neuronal cell loss is unclear; although, in many cases it may be associated with activation of the JNK pathway. In vivo knockout studies of the JNK3 gene suggest that JNK3 is an appropriate target for the development of therapeutics for the treatment of neurodegenerative diseases such as PD. Several ATP site inhibitors of JNK3 have been developed and their co-crystal structures with JNK3 reported. Most of these inhibitors, however, suffer either from lack of selectivity or from poor pharmacokinetic properties, such as low CNS penetration. In the first part of the seminar, the discovery and development, using structure-based drug design, of novel thiophene amide based active site, CNS penetrant, JNK3 inhibitors will be described, and the in vivo activity of a selected one will be reported in mouse kanic acid model. Furthermore, in our search for allosteric JNK3 inhibitors, we co-crystallized JNK3, a peptide derived from JNK interacting protein 1 (JIP1), and BIRB-796, a potent allosteric p38 kinase inhibitor. BIRB-796 binds to JNK3 in a similar manner as to p38 kinase, by stabilizing the DFG loop in an out conformation. The JNK3-BIRB-796 complex structure enabled the set-up of various biophysical and computational screening systems to identify novel DFG-out loop binding allosteric inhibitors. In the second part of the seminar, I will talk about our efforts toward the therapeutic targeting of intrinsically unstructured proteins (IUPs) linked to human diseases with drug-like small molecules. I will present an approach that combines a structure-based computational docking screen followed by a binding screen by NMR spectroscopy to identify small molecule binders to IUPs. By applying this methodology on α-synuclein, whose aggregation behavior is a central feature of PD, we find using fragment probe mapping calculations that small molecule binding pockets exist within the ensemble of conformations describing α-synucleinin solution. Moreover, a novel drug-like small molecule is identified by our screening approach, which interacts as a monomer with native monomeric α-synuclein and modulates its aggregation. The screening approach presented here has the potential to identify additional functional small molecule binders to α-synuclein, and to other IUPs, and represents a powerful approach towards the rational structure-based drug design for IUPs.

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