Molecular docking and analysis of conformation adopted by tetrapeptide inhibitors into active site of thrombin

COMP 189

Cristina C. Clement, cclement_us@yahoo.com, Chemistry Department, Lehman College, City University of New York (CUNY), 250 Bedford Park BLVD West, Bronx, New York City, NY 10468 and Manfred Philipp, Chemistry Department, Lehman College, City University of New York, 250 Bedford Park BLVD West, Bronx, New York City, NY 10468.
In silico structure-based design and screening of reversible tetrapeptides inhibitors [sequence space: D-Phe-Pro-D-Arg-P1'-CONH2] for thrombin was performed by docking peptides into active site of thrombin target 1ABJ.pdb using the softwares “SCULPT”–from MDL and BioMedCAche from Fujitsu. The P1' position was varied with D and L amino acids. The advanced molecular mechanics (MM) force–field provided by the same softwares was used to assess the structural fitness of the ligand into each of the S1', S1, S2 and S3 subpockets of thrombin (based on van der Waals and electrostatics interactions). A structure-activity relationship (SAR) for tetrapetides was performed using in vitro assays for thrombin inhibition. There is a 2 to 500 fold experimentally determined difference between the Kis of peptide inhibitors having one single variation at P1'. The analysis of the structural models together with the Ki obtained experimentally suggests that the tetrapeptides differing in one single amino acid at P1' position are adopting different conformations into active site of thrombin which might be the basis for their significant differences in their inhibitory potential.