Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand-based drug design.

Joana Magalhães, Nina Franko, Giannamaria Annunziato, Martin Welch, Stephen K Dolan, Agostino Bruno, Andrea Mozzarelli, Stefano Armao, Aigars Jirgensons, Marco Pieroni, Gabriele Costantino, Barbara Campanini

Journal: Journal of enzyme inhibition and medicinal chemistry 2018;33(1):1444-1452

PMID: 30221554

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Abstract

Several bacteria rely on the reductive sulphur assimilation pathway, absent in mammals, to synthesise cysteine. Reduction of virulence and decrease in antibiotic resistance have already been associated with mutations on the genes that codify cysteine biosynthetic enzymes. Therefore, inhibition of cysteine biosynthesis has emerged as a promising strategy to find new potential agents for the treatment of bacterial infection. Following our previous efforts to explore OASS inhibition and to expand and diversify our library, a scaffold hopping approach was carried out, with the aim of identifying a novel fragment for further development. This novel chemical tool, endowed with favourable pharmacological characteristics, was successfully developed, and a preliminary Structure-Activity Relationship investigation was carried out.

Address: a P4T group, Department of Food and Drug , University of Parma , Parma , Italy.; b Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug , University of Parma , Parma , Italy.; c Department of Biochemistry , Cambridge University , Cambridge , United Kingdom.; d Experimental Therapeutics Program , IFOM - The FIRC Institute for Molecular Oncology Foundation , Milano , Italy.; b Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug , University of Parma , Parma , Italy.; e National Institute of Biostructures and Biosystems , Rome , Italy.; f Institute of Biophysics, CNR , Pisa , Italy.; g Centro Interdipartimentale "Biopharmanet-tec", Università degli Studi di Parma , Parma , Italy.; h Latvian Institute of Organic Synthesis , Riga , Latvia.; a P4T group, Department of Food and Drug , University of Parma , Parma , Italy.; i Centro Interdipartimentale Misure (CIM)'G. Casnati', University of Parma , Parma , Italy.

DOI: 10.1080/14756366.2018.1512596

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MeSH Terms: Anti-Bacterial Agents, Bacteria, Binding Sites, Biological Assay, Computer Simulation, Cysteine Synthase, DNA, Recombinant, Drug Design, Ligands, Models, Molecular, Small Molecule Libraries, Structure-Activity Relationship