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

Journal of Enzyme Inhibition and Medicinal Chemistry

Stefano Armao¹  Martin Welch²  Stephen K. Dolan²  Agostino Bruno³  Nina Franko⁴  Barbara Campanini⁴  Andrea Mozzarelli⁵  Aigars Jirgensons⁶  Marco Pieroni⁷  Joana Magalhães⁷  Giannamaria Annunziato⁷  Gabriele Costantino⁸ 

[1] Centro Interdipartimentale “Biopharmanet-tec”, Università degli Studi di Parma, Parma, Italy;Department of Biochemistry, Cambridge University, Cambridge, United Kingdom;Experimental Therapeutics Program, IFOM – The FIRC Institute for Molecular Oncology Foundation, Milano, Italy;Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug, University of Parma, Parma, Italy;Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug, University of Parma, Parma, Italy;National Institute of Biostructures and Biosystems, Rome, Italy;Institute of Biophysics, CNR, Pisa, Italy;Latvian Institute of Organic Synthesis, Riga, Latvia;P4T group, Department of Food and Drug, University of Parma, Parma, Italy;P4T group, Department of Food and Drug, University of Parma, Parma, Italy;Centro Interdipartimentale Misure (CIM)’G. Casnati’, University of Parma, Parma, Ital;

关键词: Scaffold hopping;    fragments;    O-acetylserine sulphhydrylase;    medicinal chemistry;    pyrazoles;    ligand-based drug design;   

DOI  :  10.1080/14756366.2018.1512596

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY