We present a new approach to preparing receptor structures for virtual screening, called consensus Induced-Fit Docking IFD (cIFD), that optimizes the protein binding site in the simultaneous presence of several bound ligands. This approach results in a single binding site structure, thereby making the virtual screening computationally efficient, while also allowing for the binding of diverse active chemotypes. First, we validate this method on a set of structures from the DUD database and show that the method is effective at retrieving diverse actives. We then demonstrate the effectiveness of cIFD in an actual drug discovery program where we discover novel small molecule nuclear export inhibitors targeting the site of interaction between exportin-1/Crm1 and its cargo proteins.

Consensus induced fit docking (cIFD): An approach for binding site optimization using multiple simultaneous ligands to improve chemical coverage in virtual screening

243rd National Meeting (2012)

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