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Fragment‐Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition
Author(s) -
Englert Lisa,
Silber Katrin,
Steuber Holger,
Brass Sascha,
Over Björn,
Gerber HansDieter,
Heine Andreas,
Diederich Wibke E.,
Klebe Gerhard
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000084
Subject(s) - thermolysin , fragment (logic) , autodock , virtual screening , in silico , drug discovery , chemistry , ligand efficiency , computational biology , lead compound , combinatorial chemistry , ligand (biochemistry) , cheminformatics , computer science , enzyme , biochemistry , biology , receptor , computational chemistry , algorithm , trypsin , in vitro , gene
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 μ M , thus they provide a good starting point for further hit evolution in a tailored lead design.