Discovery of a novel serine protease inhibitor utilizing a structure-basedand experimental selection of fragments technique

We report a set of strategies to develop novel ligands (Structure Based and Experimental Selection of Fragments: SbE-SF). First, a docking simulation utilizing DOCK3.5 is performed in order to screen the fragment database, wh ich was generated with the in-house program FRAGMENT++ specifically for doc king simulation purposes. Although the affinity of these small molecules (f ragments) is expected to be low, the affinity of fragments selected by comp utation is assayed by experiment to determine which ones can be potent inhi bitors. After determining such key fragments, additional fragments are atta ched to the key ones in order to increase the binding affinity,taking into account the binding modes predicted by computation. This method has been ap plied to a thrombin inhibitor study, resulting in the discovery of a novel inhibitor exhibiting pIC(50) = 7.9.