10th EFMC Short Course on Medicinal Chemistry

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Course Outline

Protein-Protein Interactions (PPIs) lie at the heart of almost every physiological process and every disease. With a recently estimated number of 300,000 in humans, the possibilities for therapeutic intervention are significantly larger compared to ‘classical’ drug targets. While this potential is up to now largely untapped, some successful examples have shown that PPIs can be modulated by drug-like small molecules, natural products and peptides.

Specific features of PPIs as drug targets - in comparison to conventionally addressing e.g. enzymes - will be discussed, followed by a broad overview of the field, techniques to discover modulators of PPIs,  and - in more detail - a number of case studies on successful PPI intervention will be presented. Speakers include a selection of top-scientists active in the field of PPI, both from industry and academia.

Abstracts of the Presentations

Nuclear Receptor Protein-Protein Interactions
Prof. Luc Brunsveld (EINDHOVEN UNIVERSITY OF TECHNOLOGY, the Netherlands)

The nuclear receptor – cofactor interaction is the key protein – protein interaction that transfers ligand induced changes in the nuclear receptor conformation to the transcriptional machinery. A molecular understanding of this process and its regulation is necessary to fully control and predict the effects of nuclear receptor modulation, either via classical ligands or via direct modulation of this interaction and for the discovery of new entries to target these important drug targets. Using examples on specific nuclear receptors, insights into these PPIs are conferred. Examples of inhibition and stabilization of these PPIs will be presented and the regulation of this PPI via post-translational modifications discussed.

Modern Methods for Targeting Low Affinity Protein-Protein Interactions: Structure and Function

Prof. Anna Mapp (UNIVERSITY OF MICHIGAN, United States)

Within the chemical space of protein-protein interactions (PPIs), transient, modest affinity PPIs play a central role in a variety of cellular functions, including protein folding and transcription. Additionally, mis-regulation of this class of PPIs is at the heart of diseases ranging from cancer to neurodegenerative disorders. Despite their importance and their prevalence, transient and modest affinity PPIs are often classified as ‘undruggable’, with few successful strategies for small molecule modulator discovery. The challenge is multi-variable: the binding partners often have significant disorder and are thus difficult to characterize structurally alone or in complex; the surface area of the area of the interactions are considerably larger than typical protein-ligand interactions and the strengths of the interactions are modest. We will discuss two new strategies for the discovery of small molecule modulators of PPIs that play a key role in transcription, strategies that have produced molecules with unique potency and specificity profiles. In the first instance, small molecule co-chaperones have been discovered through the Tethering screening strategy, leading to covalent ligands that facilitate structural characterization of dynamic proteins by X-ray crystallography. Additionally, the ligands modulate the assembly state of the transcriptional coactivator target for functional applications. In the second strategy, an iterative screening method will be described that facilitates the discovery of modulators with mixed orthosteric/allosteric mechanistic features.

Structure-based Guided Development & Experimental Validation of a Focused Chemical Library Dedicated to Orthosteric Modulation of Protein-Protein Interactions

Dr Xavier MORELLI (CNRS, France)

We have recently developed 2P2IDB, a hand-curated structural database dedicated to PPI with known orthosteric inhibitors ([1,2], http://2p2idb.cnrs-mrs.fr). Analysis of the small molecule inhibitors present in 2P2IDB led us to propose the ‘rule-of-four’ as a guideline to characterize PPI inhibitors [3]. Using dedicated support vector machine approaches, we have developed 2P2IHUNTER, a tool for filtering potential orthosteric PPI modulators from large collection of compounds [4]. This innovative tool has been applied to a set of 8.3 million compounds from the “big vendors” to design several in silico PPI-focused chemical libraries [5]. Compounds corresponding to medicinally important privileged structures identified as core structures in numerous therapeutics were prioritized in a medicinal oriented version of the library. The library was filtered with carbon bond saturation index (Fsp3) to escape from flatland, which resulted in a structurally diverse chemical library, 2P2I3D, of 1,664 compounds [5]. The molecules have been purchased from the providers, stored in 384-well plates and evaluated using Homogeneous Time-Resolved Fluorescence spectroscopy (HTRF) on the AD2P Platform (part of the National Network of the French Screening Platform, Marseille) and in collaboration with several Biotech companies against a standard set of PPI targets (P53/MDM2; TCF/bcatenin; BRD4 Bromodomain; PDZ domains and viral PPIs) to evaluate their ability to enhance hit rates in general screening campaigns (2P2IHTS Program). The design and molecular properties of the in silico chemical library and the HTS results will be discussed during this presentation with a specific emphasis on Bromodomains and PDZ domains.

Design and Synthesis of PPI-focussed Chemical Libraries

Protein-protein interactions (PPIs) are attracting broader attention in life sciences and drug discovery due to their involvement in the modulation of key physiological functions. Here, the availability of compounds that are able to bind to the PPI of interest is paramount. The presentation will detail current concepts and approaches to the design of compound libraries that are biased towards PPIs and describe the associated synthetic strategies.

Design and Evaluation of biophysical Assays for the Identification of  PPI-Modulators

Dr. Alexander WOLF (LEAD DISCOVERY, Germany)

One of the promising approaches in modern drug discovery is the modulation of protein-protein interactions (PPIs) with small, drug-like molecules. Not only is the number of potentially addressable PPI targets with estimates between 130.000 and 650.000 significantly higher than those of single protein targets, but also a number of natural products and molecules from drug discovery initiatives illustrates that PPIs are addressable with small molecules. However, despite these encouraging vantage points, identification and optimization of small-molecule modulators of PPIs still poses a formidable challenge. The first part of the talk will focus on the design and setup of homogenous assay formats that are in common use in HTS campaigns when investigating PPIs, mainly  TR-FRET and AlphaScreen (Perkin Elmer). The second part of the talk will center on high kinetic content assays used for an in depth analysis of the PPI modulation, mainly Surface Plasmon resonance (SPR) and MicroScale Thermophoresis (MST).

Stabilization of PPIs: the Other Side of PPI Modulation

In this part of the workshop we will discuss examples of natural products but also drug development molecules that confer their physiological activity by stabilizing PPIs. This will include natural products like rapamycin, FK506, brefeldin A, and forskolin but also drugs and drug-like molecules like tafamidis, trifluoroperazine, RO2343, dexrazoxane, and BMS493. These examples will be complemented by our own work on stabilizers and inhibitors of 14-3-3 PPIs.

Developing Small Molecule Inhibitors of Bromodomain-Based Protein-Protein Interactions
Dr Stuart J. CONWAY (UNIVERSITY OF OXFORD, United Kingdom)

Description to be added soon!

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