Journal of Developing Drugs
Open Access
ISSN: 2329-6631
+44 1478 350008
ISSN: 2329-6631
+44 1478 350008
Milon Mondal
University of Groningen, The Netherlands
Posters & Accepted Abstracts: J Develop Drugs
Structure-based design (SBD) is a powerful strategy to design and/or optimize bioactive compounds. Whereas, de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit discovered by other means. Dynamic combinatorial chemistry has emerged as a powerful strategy to identify ligands for biological targets. In a dynamic combinatorial library (DCL), the connection bonds between the building blocks are reversible and continuously being made and broken. The composition of a DCL will respond to the addition of a target protein that selectively binds one or more library members and will extract such member(s) from the DCL. Here, we have demonstrated that the novel combination of de novo SBD and DCC is a highly efficient hit-identification strategy. We have designed a library of potential inhibitors (acyl hydrazones) generated from 5 aldehydes and 5 hydrazides and used DCC to identify the best binder(s). Upon addition of the aspartic protease endothiapepsin, the protein-bound library member(s) were characterized by saturation-transfer difference NMR spectroscopy (STD-NMR). The ligands identified were synthesized separately and tested for their biological activity using an enzyme-based fluorescence assay and shown to have IC50 values in the double-digit micromolar range. Subsequent co-crystallization experiments validated the predicted binding mode of the two most potent inhibitors, constituting a proof of concept that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization.
Email: m.mondal@rug.nl