D-EXP015

=Objective= To dock CombiUgi UClib005 (1512 compounds) against [|falcipain-2] using the covalent docking option of GOLD. This library has chloroacetic acid as a common component to serve as the electrophile in the irreversible docking.

=Procedure= The target of interest is the falcipain-2 enzyme. A crystal structure was published in Jan 2009 ([|3BPF], [|Kerr et al]) with the covalently-bound inhibitor E64.

The crystallographic unit contains 4 monomers, of which the B monomer is identified (in the paper) as of highest quality ("our structural analyses involve monomer B from FP2 and monomer A from FP3, the best resolved monomer from each complex"). The B monomer was extracted, waters removed and hydrogens added (with GOLD's GUI). The histidine close to the cysteine SH was deprotonated at the pro ("near") N (in common with how other proteases were prepared by Astex in their Diverse Set).

The dataset of Ugi products was supplied as SMILES strings. The Cl was moved to atom position 1 (for convenience when setting up the covalent docking). CORINA was used to create all stereoisomers and add hydrogens ("./corina -i t=smiles -d stergen -d wh ClAtStart.txt inhibitors.sdf"). Finally, the Cl was replaced by S (required for covalent docking).

The dataset was covalently docked using each of Goldscore, ASP and Chemscore using GOLD's auto settings. Only the top scoring pose for each stereoisomer was retained.

=Results=

In assessing the results, only the top scoring stereoisomer for a particular molecule is used Ranked Suicide Inhibitor Library-1 according to Goldscore [|Results spreadsheet]

=Discussion=

Of the three scoring functions, only Goldscore was able to reproduce the crystallographic pose of E64 //**and**// score it highly, albeit not as highly as we would wish. (Note to self: It might be worth including other known actives to see the performance - especially known actives which are closer in structure to the Ugi products.)

The results are given for Goldscore. The top-ranked hit looks like a big ball of grease and so it might not be a reliable lead. The other top-ranked hits seem reasonable though.

=Conclusion=