Periodic Reporting for period 2 - FRAGNET (FRAGments training NETwork) Reporting period: 2018-03-01 to 2020-02-29 Summary of the context and overall objectives of the project The Marie Skłodowska-Curie Innovative Training Network (ITN) FRAGNET was set up to train fifteen Early Stage Researchers (ESRs) in Fragment-Based Lead Discovery (FBLD, also known as Fragment-Based Drug Design FBDD). 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 ligands can be used as pharmacological tools and starting points for drug discovery. Europe has played a prominent role in establishing FBLD and the FRAGNET consortium was committed to train 15 multidisciplinary FBLD scientists, as well as to develop the tools and technologies that allow industry and academia to remain competitive in this highly innovative and important research field. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Within FRAGNET, the different aspects of FBLD have been studied in separate Work Packages (WP). Whereas WP1 (management) and WP2 (training) focused on organizing the network as efficiently as possible, the other WPs focused on scientific progress. In WP3, new fragment libraries were developed, including novel 3D fragments and reactive fragments that can make covalent bonds with the target proteins. The libraries have been made available for (future) screening activities. In WP4, novel screening technologies and novel target classes were evaluated. Amongst others, this has resulted in applying novel biophysical screening approaches and using orthogonal screening approaches to study emerging drug targets like intrinsically disordered proteins and a variety of proteins having allosteric binding sites. In WP5, computational methods were developed that are able to guide FBLD projects, leading to several new protocols for exploring fragment-protein binding and for fragment hit evolution. Amongst others, this has resulted in approaches and protocols that are available for the broader scientific community. FBLD applications were studied in WP6, leading to new biologically active compounds and the characterisation of novel biologically relevant targets. Finally, WP7 focused on business and innovation processes in pharmaceutical sciences. Using amongst others bibliometric analyses, questionnaires and interviews, these studies explored the origin and development of FBLD, the role of individual researchers and their career development as well as the role of public-private partnerships in drug discovery. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The objectives of FRAGNET were to (a) train a cohort of ESRs across FBLD aspects and (b) develop individual research skills in either new methods in FBLD or in applying FBLD to interrogate biological systems. In the course of the programme, the ESRs developed this unique expertise in FBLD and also developed transferable skills. FRAGNET beneficiaries and partners trained the ESRs in such a way that they have all the FBLD skill sets that will make them attractive future employees in the field of pharmaceutical sciences. 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 training network has resulted in a strong collaboration between the beneficiaries and partners and significant synergy was obtained by combining the different technologies and capabilities, making a lasting impact on FBLD and the pharmaceutical sciences in Europe. The FRAGNET consortium is eager to continue the training and research activities in the future. FRAGNET logo The typical workflow of an FBLD project
