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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - AEGIS (Accelerated Early staGe drug diScovery)

Teaser

Summary

The development of potent and safe new drugs - especially for rare and neglected diseases - is one of the biggest challenges of the upcoming decades, as shown by many epidemics the last years. The aim of the AEGIS ITN is to implement the first comprehensive, cross-disciplinary, intersectorial and structured curriculum for PhD students in the European Research Area by establishing a unique training platform for the next generation of European researchers in early drug discovery. Important added value is provided through networking with European pharmaceutical companies. A main research goal of AEGIS is improving the efficiency and success of early stage drug development by combining innovative methods and techniques to tackle challenging but promising targets (i.e. protein-protein interactions), which are often neglected due to the high risk associated with their validation. AEGIS will improve the availability of a highly skilled workforce for European industries and research. It will greatly enhance the employability and the career perspectives of young researchers for academia and industry and thus promote a sustainable development in innovative drug discovery, in particular for rare and neglected diseases.
Aim 1: Train a new generation of researchers in integrated structure-based drug discovery in an open innovation collaboration between academic and industrial partners for enhancing their employability
Aim 2: Offer ESRs access to world-class expertise and infrastructure in an intersectorial and multidisciplinary research environment
Aim 3: Accelerate and improve early drug discovery by developing novel methods
Aim 4: Identify lead compounds for targets involved in rare and neglected diseases of urgent medical need
Aim 5: Form a sustainable network of academic and industrial drug discovery centers of excellence and ESRs that will last beyond the AEGIS timeline.

Work performed

INNOVATIVE APPROACHES TO DRUG DISCOVERY The AEGIS work progress is according to the plan. Screening information was gathered for active fragments to the consortium target proteins. These are now analysed for their ability to induce additional pockets and interact with transient features in the protein binding interfaces. The experimental analysis is supplemented with molecular dynamics studies performed on the targets. We are implementing novel methods using NMR and molecular dynamics simulations for the detection and utilization of transient pockets with exciting promising results. We have complemented the pharmacophore models used for computational screening with results of the transient features detected by molecular dynamics. The experimental work is performed with the trypanosomal target protein PEX14, one of the key targets in the AEGIS consortium. X-ray fragment screening has been performed and results are being analysed. The fragment information derived from screening has been used already to guide future synthesis steps. A comparative analysis of the NMR and X-ray fragment screens, regarding type and quantity of hits has been started.
EXPERIMENTAL SCREENING AND STRUCTURAL BIOLOGY In the AEGIS project, the following target proteins have been selected for in-depth fragment-based lead discovery: T. cruzi PEX14, FPPS and Mycobacterium protein-tyrosine phosphatase (MptpB), UMP kinase (UMPK) and 14-3-3/p53. Feasibility studies have been performed with well-established model systems. Furthermore, several virtual screening hits of tri-peptidic size were characterized by NMR as binders and co-crystallized with PEX14 driving the protein in alternative packing. The crystallization of FPPS, MptpB and UMPK needs to be optimized. A fragment screening at AZ using 14-3-3/p53 and the AZ fragment library resulted in two fragment hits, which could be further evolved by chemical synthesis.
MEDICINAL CHEMISTRY A fragment library was designed based on multicomponent reaction (MCR) principles and physically realized with currently >700 fragment compounds plated. The physical fragment library is available to every member of the AEGIS consortium for screening purposes. Several hits in different projects were found. Hits generated by other screening methods were taken up and optimised by medicinal chemistry methods.
COMPUTATIONAL ANALYSIS Computational approaches focused on the identification and design of inhibitors with therapeutic potential. Computational analysis connects the hit and lead finding activities through virtual screening molecular design through fragment library design and reaction, generation of SAR models, investigation of novel effector mechanisms exploiting original computational methods, including molecular dynamics (MD) and transitional functional mechanism modelling. Excellent progress has been made on these objectives and already generated novel hits for various AEGIS targets, which are being validated and further developed using experimental methods.
AEGIS TRAINING Within AEGIS, already three Training Schools were implemented with the topics: Biophysical and biochemical assays in drug discovery (University Uppsala and Ridgeview Instruments), Medicinal Chemistry (University Groningen) and Fragment-based screening, NMR, basic interaction analysis (Helmholtz Zentrum MÃ¼nchen). The schools have been extremely successful and productive both in providing excellent teaching and scientific training but also in networking the AEGIS ESRs and partners and generating novel ideas from interactions and discussions during the meetings. Next to the regular thesis committee meetings and local training and mentoring, 11 literature webinars have been already organized with active contribution and interesting and stimulating discussions by the ESRs.

Final results

The combination and comparative evaluation of NMR and crystallography-based fragment screening, co-crystallisation of fragments and compounds as well as computational studies of molecular dynamics opened new ways for the development of inhibitors for neglected disease targets. Unique computational tools and approaches available in the consortium provided novel chemical matter as inhibitors for the AEGIS targets, and thus new inhibitor classes. In the case of the AEGIS target PEX14 exciting progress has been made. This is expected to generate novel leads by the end of the AEGIS project, which will form the basis for (pre)clinical development in cooperation with industrial cooperation partners. The development of intracellular assays in LigandTracer facilitates the detection of protein interactions and will help to develop novel methodology for target validation. The set-up of a fragment library based on multicomponent reactions as well as the establishment of a virtual compound library is a valuable resource for the AEGIS consortium to develop new inhibitors. The AEGIS students benefitted from substantial and very valuable secondments with other AEGIS partners - especially with the industrial partners. The three training schools completed further strengthened AEGIS training and provided teaching with various important skills in complementary topics. Thus, AEGIS is very effective in training a new generation of multi-sectoral and multi-disciplinary scientists and AEGIS fellows are expected to strengthen and promote an innovation of drug discovery in Europe.