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Fragmenting the S100B–p53 Interaction: Combined Virtual/Biophysical Screening Approaches to Identify Ligands |
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| Authors: | Mariangela Agamennone Dr Lucia Cesari Dr Daniela Lalli Dr Elisa Turlizzi Dr Rebecca Del?Conte Dr Paola Turano Prof Stefano Mangani Prof Alessandro Padova Dr |
| Affiliation: | 1. MET Profiling Unit, Screening & Technologies Dept., Siena Biotech S.p.A. Strada del Petriccio e Belriguardo 35, 53100 Siena (Italy);2. Magnetic Resonance Center (CERM), University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino (Italy);3. Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (Italy);4. Dipartimento di Chimica, Università di Siena, Via Aldo Moro, 53100 Siena (Italy);5. Drug Design Unit, Molecular Informatics Dept., Siena Biotech S.p.A. Strada del Petriccio e Belriguardo 35, 53100 Siena (Italy), Fax: (+39)?0577‐381‐208 |
| Abstract: | S100B contributes to cell proliferation by binding the C terminus of p53 and inhibiting its tumor suppressor function. The use of multiple computational approaches to screen fragment libraries targeting the human S100B–p53 interaction site is reported. This in silico screening led to the identification of 280 novel prospective ligands. NMR spectroscopic experiments revealed specific binding at the p53 interaction site for a set of these compounds and confirmed their potential for further rational optimization. The X‐ray crystal structure determined for one of the binders revealed key intermolecular interactions, thus paving the way for structure‐based ligand optimization. |
| Keywords: | fragment‐based drug design NMR spectroscopy protein– protein interactions X‐ray diffraction |