3NLW

Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(((3S,4S)-4-(2-(2,2-Difluoro-2-(piperidin-2-yl)ethylamino)ethoxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine

Summary for 3NLW

• Entry DOI: 10.2210/pdb3nlw/pdb
• Related: 3NLD 3NLE 3NLF 3NLG 3NLH 3NLI 3NLJ 3NLK 3NLM 3NLN 3NLO 3NLP 3NLQ 3NLR 3NLT 3NLU 3NLV 3NLX 3NLY 3NLZ 3NM0 3NNY 3NNZ
• Descriptor: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase, heme thiolate enzyme, inhibitor, oxidoreductase
• Biological source: Rattus norvegicus (brown rat,rat,rats)
• Cellular location: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• Total number of polymer chains: 2
• Total formula weight: 100319.03

Authors

Li, H.,Delker, S.L.,Poulos, T.L. (deposition date: 2010-06-21, release date: 2011-01-19, Last modification date: 2023-09-06)

Primary citation

Xue, F.,Li, H.,Delker, S.L.,Fang, J.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase.
J.Am.Chem.Soc., 132:14229-14238, 2010

PubMed Abstract: In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF(2) moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K(i) of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.

PubMed: 20843082
DOI: 10.1021/ja106175q

Experimental method

X-RAY DIFFRACTION (2.1 Å)