Mapping the active site polarity in structures of endothelial nitric oxide synthase heme domain complexed with isothioureas.

Department of Molecular Biology & Biochemistry and Physiology & Biophysics and Program in Macromolecular Structure, University of California, Irvine 92697-3900, USA.

Analyzing the active site topology and plasticity of nitric oxide synthase (NOS) and understanding enzyme-drug interactions are crucial for the development of potent, isoform-selective NOS inhibitors. A small hydrophobic pocket in the active site is identified in the bovine eNOS heme domain structures complexed with potent isothiourea inhibitors: seleno analogue of S-ethyl-isothiourea, S-isopropyl-isothiourea, and 2-aminothiazoline, respectively. These structures reveal the importance of nonpolar van der Waals contacts in addition to the well-known hydrogen bonding interactions between inhibitor and enzyme. The scaffold of a potent NOS inhibitor should be capable of donating hydrogen bonds to as well as making nonpolar contacts with amino acids in the NOS active site.

PMID: 11051558 [PubMed - indexed for MEDLINE]