title: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.
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.
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747, AG, Groningen, The Netherlands.
authors.forename: Milon
authors.identifier: 0000-0002-1613-7269
authors.initials: M
authors.lastname: Mondal
authors.affiliation: Institute of Pharmaceutical Chemistry, Marbach Weg 6, 35032, Marburg, Germany.
authors.forename: Nedyalka
authors.initials: N
authors.lastname: Radeva
authors.affiliation: Centre for Systems Chemistry, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747, AG, Groningen, The Netherlands.
authors.forename: Hugo
authors.identifier: 0000-0001-8266-2881
authors.initials: H
authors.lastname: Fanlo-Virgós
authors.affiliation: Centre for Systems Chemistry, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747, AG, Groningen, The Netherlands.
authors.forename: Sijbren
authors.initials: S
authors.lastname: Otto
authors.affiliation: Institute of Pharmaceutical Chemistry, Marbach Weg 6, 35032, Marburg, Germany.
authors.forename: Gerhard
authors.identifier: 0000-0002-4913-390X
authors.initials: G
authors.lastname: Klebe
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747, AG, Groningen, The Netherlands. A.K.H.Hirsch@rug.nl.
authors.forename: Anna K H
authors.identifier: 0000-0001-8734-4663
authors.initials: AK
authors.lastname: Hirsch
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase
keywords: X-ray diffraction; dynamic combinatorial chemistry; fragment-based drug design; inhibitors; proteases