1. Fragment-Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition
- Author
-
Andreas Heine, Gerhard Klebe, Sascha Brass, Hans-Dieter Gerber, Björn Over, Katrin Silber, Lisa Englert, Wibke E. Diederich, and Holger Steuber
- Subjects
In silico ,Fragment-based lead discovery ,Thermolysin ,Crystallography, X-Ray ,Biochemistry ,Fragment (logic) ,Drug Discovery ,Computer Simulation ,Protease Inhibitors ,General Pharmacology, Toxicology and Pharmaceutics ,Databases, Protein ,Pharmacology ,Virtual screening ,Binding Sites ,Ligand efficiency ,Aspirin ,Drug discovery ,Chemistry ,Organic Chemistry ,AutoDock ,Combinatorial chemistry ,Protein Structure, Tertiary ,Drug Design ,Molecular Medicine ,Software - 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.
- Published
- 2010
- Full Text
- View/download PDF