Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment‐Based Drug Design Facilitated by Dynamic Combinatorial Chemistry. Issue 32 (12th July 2016)

• Record Type: Journal Article
• Authors: Mondal, Milon; Radeva, Nedyalka; Fanlo‐Virgós, Hugo; Otto, Sijbren; Klebe, Gerhard; Hirsch, Anna K. H.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 32(2016)
• Page Start: 9422
• Page End: 9426
• Publication Date: 2016-07-12
• Subjects: dynamic combinatorial chemistry -- fragment-based drug design -- inhibitors -- proteases -- X-ray diffraction; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201603074
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Fragment‐based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit‐identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X‐ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis‐acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240‐fold improvement in potency compared to the parent hits. Subsequent X‐ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit‐identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit‐to‐lead optimization. Abstract : Better together : The synergistic combination of fragment linking and dynamic combinatorial chemistry represents a powerful and efficient strategy for accelerating hit identification and optimization, with the potential to afford new lead compounds. The most potent inhibitor of the aspartic protease endothiapepsin identified in this way exhibits an IC50 value of 54 nm, which represents a 240‐fold improvement in potency compared to the parent hits.