Fragment‐Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition |
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Authors: | Lisa Englert Katrin Silber Dr. Holger Steuber Prof. Dr. Sascha Brass Dr. Björn Over Hans‐Dieter Gerber Andreas Heine Dr. Wibke E. Diederich Prof. Dr. Gerhard Klebe Prof. Dr. |
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Affiliation: | 1. Philipps‐Universit?t Marburg, Institut für Pharmazeutische Chemie, Marbacher Weg 6, 35032 Marburg (Germany), Fax: (+49)?6421‐28‐28994;2. Present address: Institut für Biochemie – Universit?t zu Lübeck Ratzeburger Allee 160, 23538 Lübeck (Germany) |
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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 Ki values as low as 128 μM , thus they provide a good starting point for further hit evolution in a tailored lead design. |
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Keywords: | drug discovery fragment‐based design inhibitors medicinal chemistry virtual screening X‐ray diffraction |
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