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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - FRAGNET (FRAGments training NETwork)

Teaser

Summary

The Marie SkÅ‚odowska-Curie Innovative Training Network (ITN) FRAGNET is set up to train a new generation of Early Stage Researchers (ESRs) in the much needed holistic understanding of the many aspects of Fragment-Based Lead Discovery (FBLD, also known as Fragment-Based Drug Design FBDD) thereby enabling them to use the different methods and technologies to develop the next generation of medicines. In the last ten years, FBLD has proven to be an effective approach towards the discovery of small molecule compounds (ligands) that can bind to biological target molecules such as proteins and nucleic acids. FBLD projects begin with screening low molecular weight compounds (so-called fragments) against a biological target (most often a protein). This requires a fragment library and an experimental method to detect binding. Once hits have been identified, the structure of hit fragments binding to the target is determined by X-ray crystallography, NMR methods or molecular modelling approaches. The fragments are then evolved to compounds with higher affinity and activity by structure-based design and synthetic chemistry. The resulting compounds can be used as pharmacological tools and starting points for drug discovery.

Work performed

Within FRAGNET, the different aspects of FBLD are studied in separate Work Packages (WP). Whereas WP1 (management) and WP2 (training) focus on organizing the network as efficiently as possible, the other WPs focus on scientific progress. In WP3, new fragment libraries are being developed, with collaborative efforts on generating novel 3D fragments and covalent fragment binders. The obtained chemical entities are now evaluated on various FRAGNET targets. In WP4, novel screening technologies and novel target classes are being evaluated. In WP5, computational methods are being developed that are able to support FBLD projects, leading to several new protocols for exploring fragment-protein binding and for fragment hit evolution. FBLD applications are being studied in WP6, currently incorporating results from all other WPs (libraries, technologies, computational methods) in order to find new biologically active compounds or investigate novel biologically targets. Finally, WP7 is focusing on dissemination and investigates innovation processes in the pharmaceutical sciences. The ongoing studies have already resulted in a thorough bibliometric analysis that describes the origin and development of FBLD and lead to a better understanding of the value and contribution of public and private entities in pharmaceutical research.

Final results

The objectives of FragNet are to (a) train a cohort of ESRs across FBLD methods and (b) develop individual skills in research into either new methods in FBLD or to apply FBLD to interrogate biological systems. We expect our ESRs will develop unique expertise in FBLD, and embedded in the FragNet network, the ESRs will have the ideal start for their career, either in industry or academia. They will become leaders in the development of this new technology and ultimately become the leaders that will deliver the next generation of many different drug candidates.
FragNet originates from scientists who are among the pioneers from industry and academia that have been pushing the scientific boundaries of FBLD for more than a decade. The FragNet participants are now joining forces to set up the research and training programme to tackle some of the remaining challenges and opportunities. We have never before had the opportunity to work together so closely, and we expect huge synergies from the pooling of our combined technologies and expertise. We expect that the result of our efforts will be highly influential on pharmaceutical sciences, including SMEs, big pharmaceutical companies and academia.