3RQP

Structure of the endothelial nitric oxide synthase heme domain in complex with 6-{[(3R,4R)-4-(2-{[(2R/2S)-1-(3-fluorophenyl)propan-2-yl]amino}ethoxy)pyrrolidin-3-yl]methyl}-4-methylpyridin-2-amine

Summary for 3RQP

• Entry DOI: 10.2210/pdb3rqp/pdb
• Related: 3RQJ 3RQK 3RQL 3RQM 3RQN 3RQO
• Descriptor: Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (9 entities in total)
• Functional Keywords: oxidoreductase, enzyme-inhibitor complex, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Bos taurus (bovine,cow,domestic cattle,domestic cow)
• Cellular location: Cell membrane : P29473
• Total number of polymer chains: 2
• Total formula weight: 102378.21

Authors

Li, H.,Delker, S.L.,Poulos, T.L. (deposition date: 2011-04-28, release date: 2012-05-02, Last modification date: 2023-09-13)

Primary citation

Li, H.,Xue, F.,Kraus, J.M.,Ji, H.,Labby, K.J.,Mataka, J.,Delker, S.L.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase.
Bioorg.Med.Chem., 21:1333-1343, 2013

PubMed Abstract: Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl-containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which resulted in decreased inhibitory activity of these inhibitors compared to the parent compound. Nonetheless, three of them exhibited double-digit nanomolar inhibition with high nNOS selectivity on the basis of in vitro enzyme assays. Crystal structures of nNOS and eNOS with these inhibitors bound provide a basis for detailed structure-activity relationship (SAR) studies. The conclusions from these studies will be used as a guide in the future development of selective NOS inhibitors.

PubMed: 23352768
DOI: 10.1016/j.bmc.2012.12.019

Experimental method

X-RAY DIFFRACTION (2.35 Å)