Computer modeling of selective regions in the active site of nitric oxide synthases: implication for the design of isoform-selective inhibitors.
Article Details
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Ji H, Li H, Flinspach M, Poulos TL, Silverman RB
Computer modeling of selective regions in the active site of nitric oxide synthases: implication for the design of isoform-selective inhibitors.
J Med Chem. 2003 Dec 18;46(26):5700-11.
- PubMed ID
- 14667223 [ View in PubMed]
- Abstract
Selective inhibition of nitric oxide synthase (NOS) isoforms has great therapeutic potential in the treatment of certain disease states arising from the pathological overproduction of nitric oxide. In this study three structures of each NOS isoform were employed to examine selective regions in the active site using the GRID/CPCA approach. In the GRID calculations, 10 probes covering hydrophobic, steric, and hydrogen-bond-acceptor and -donor interactions were used to calculate the molecular interaction fields (MIFs) in the active site. The side chain flexibility of the residues and the grid spacings were considered at the same time. Consensus principal component analysis (CPCA) was applied to analyze the MIFs differences in the active site between the NOS isoforms. By combining the cutout tool with GRID/CPCA pseudofield differential plots, several selective regions in the active site were identified. The selectivity analysis showed that the most important determinants for NOS inhibitor selectivity are hydrophobic and charge-charge interactions. Twenty-five inhibitors of NOS were then docked into the active site using the program AutoDock3.0. The regions identified as being important for selectivity by this method are in excellent agreement with inhibitor structure-activity relationships. A rational usage of the selective region described in this work should make it possible to develop NOS isoform-selective inhibitors.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) L-N(omega)-Nitroarginine-2,4-L-diaminobutyric amide Nitric oxide synthase, brain Ki (nM) 330 N/A N/A Details L-N(omega)-Nitroarginine-2,4-L-diaminobutyric amide Nitric oxide synthase, endothelial Ki (nM) 245000 N/A N/A Details N-{(4S)-4-Amino-5-[(2-aminoethyl)amino]pentyl}-N'-nitroguanidine Nitric oxide synthase, brain Ki (nM) 290 N/A N/A Details N-{(4S)-4-Amino-5-[(2-aminoethyl)amino]pentyl}-N'-nitroguanidine Nitric oxide synthase, endothelial Ki (nM) 524000 N/A N/A Details