3D-QSAR with CoMFA model of prolylendopeptidase substrates

The prolylendopeptidase (PEP) is the proteolytic enzyme, which plays an ess ential role in the regulation of some processes in central nervous system, such as memory, learning and behavior. It was shown that PEP activity chang es at different diseases, like Parkinsons or Alzheimer's diseases, and some PEP inhibitors are used in therapy. At present time the discovery of new t ypes of PEP inhibitors are the actual task. In this study the structure of PEP active site was analyzed by 3D-QSAR with CoMFA methods using of 12 PEP substrates. The designed pharmacophore model assumes that substrates interact with PEP active site by pyrrolidol ring o f proline residue and by hydrogen bonding. The 3-D-QSAR + CoMFA model of PEP substrates propose that the hydrophobic b onds play the essential role in substrate interaction with enzyme. This mod el reveals the important steric acid electrostatic areas around the molecul es and the presence of substituents controls the PEP activity for substrate s. Analysis of obtained data allows to assume, that substrate binding in PE P active site causes essential perturbations of substrate structure. This e ffect mainly depends on chemical nature of the amino acid side chain, locat ed near to proline.