MEDI 74 |
| We used the structure-based design approach to generate in silico libraries of peptides with potential inhibitory activity against Factor VII-a. The 1qfk.pdb was used as template in docking experiments which were performed using the software “SCULPT” from MDL. We first generated a set of peptides with different chain length and different sequence space and assessed the free energy of interaction between the protein target and the ligands using the MMFF94 (force-field) built-in the software SCULPT. Both the van der Waals and the electrostatic interactions were used to generate the free energy of interaction between Factor VII-a and the peptides ligands during rigid docking experiments. The peptide Gly-Ser-Ala-D-Phe-Phe-Arg-CONH2 was discovered as a lead compound in the original series of peptides and was synthesized using F-moc solid phase peptide chemistry approach. In vitro kinetics of Factor VII-a inhibition showed that this reversible peptide inhibitor has an IC-50 of 20 uM. Ki (inhibitory constant) was estimated to be 2 nM and is the first peptide reported in the field to be a powerful inhibitor of Factor VII-a, supporting the structure-based design as a reliable approach to generate new lead compounds and also to optimize the leads by using powerful docking experiments and reliable scoring functions. |
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |