3f2p

Publication Abstract from PubMed

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 muM, thus they provide a good starting point for further hit evolution in a tailored lead design.

Fragment-Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition.,Englert L, Silber K, Steuber H, Brass S, Over B, Gerber HD, Heine A, Diederich WE, Klebe G ChemMedChem. 2010 Apr 14. PMID:20394106^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.