title: Fragment-based lead discovery: screening and optimizing fragments for thermolysin inhibition.
abstract: Fragment-based drug discovery has gained a foothold in today's lead identification processes. We present the application of in silico fragment-based screening for the discovery of novel lead compounds for the metalloendoproteinase thermolysin. We have chosen thermolysin to validate our screening approach as it is a well-studied enzyme and serves as a model system for other proteases. A protein-targeted virtual library was designed and screening was carried out using the program AutoDock. Two fragment hits could be identified. For one of them, the crystal structure in complex with thermolysin is presented. This compound was selected for structure-based optimization of binding affinity and improvement of ligand efficiency, while concomitantly keeping the fragment-like properties of the initial hit. Redesigning the zinc coordination group revealed a novel class of fragments possessing K(i) values as low as 128 microM, thus they provide a good starting point for further hit evolution in a tailored lead design.
authors.affiliation: Philipps-Universität Marburg, Institut für Pharmazeutische Chemie, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Englert
authors.forename: Katrin
authors.initials: K
authors.lastname: Silber
authors.forename: Holger
authors.initials: H
authors.lastname: Steuber
authors.forename: Sascha
authors.initials: S
authors.lastname: Brass
authors.forename: Björn
authors.initials: B
authors.lastname: Over
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Gerber
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D001241:Aspirin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D011480:Protease Inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012984:Software; D013820:Thermolysin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D011480:Protease Inhibitors; D013820:Thermolysin; D001241:Aspirin