Discovery of Highly Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase by Fragment Hopping

Ji, Haitao; Li, Huiying; Martásek, Pavel; Roman, Linda J.; Poulos, T.L.; Silverman, Richard B.

doi:10.1021/jm801220a

Cited by 80 publications

(103 citation statements)

References 67 publications

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“…Nevertheless, the Poulos and Silverman labs have successfully elucidated the structural basis for a group of highly selective nNOS inhibitors and designed new classes of more potent drug-like inhibitors (22,23,52). In our studies, we have tested a group of these potent nNOS inhibitors with distinct K i values for nNOS, iNOS, and eNOS, which efficiently inhibited UVA-induced NO production and reduced the invasion potential of metastatic melanoma cells.…”

Section: Inhibition Of Nnos With Novel Inhibitorsmentioning

confidence: 99%

Targeting Nitric Oxide Signaling with nNOS Inhibitors As a Novel Strategy for the Therapy and Prevention of Human Melanoma

Yang

Misner

et al. 2013

Antioxidants & Redox Signaling

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Aims: Our previous studies have shown that nitric oxide (NO) plays an important role in increasing the invasion and proliferation of human melanoma cells, suggesting that targeting NO signaling may facilitate therapy and prevention. Neuronal nitric oxide synthase (nNOS) is present in melanocytes, a cell type that originates from the neural crest. The aims of this study were to determine the role of nNOS in melanoma progression and the potential antitumor effects of novel synthesized nNOS inhibitors. Results: In vitro studies demonstrated abundant expression of nNOS in melanoma compared to melanocytes, which was inducible by ultraviolet radiation and was associated with increased NO generation. nNOS was also detected in melanoma biopsies that increased with disease stage. Knockdown of nNOS in melanoma cells diminished L-arginine-induced NO production; the metastatic capacity was also reduced as well as the levels of MMP-1, Bcl-2, JunD, and APE/Ref-1. Similar inhibition of NO and invasion potential was observed utilizing novel, highly selective nNOS inhibitors. In three-dimensional human skin reconstructs, the nNOS inhibitor cpd8 effectively reversed the melanoma overgrowth stimulated by NO stress. Innovation: Our work lays the foundation for development of clinical ''drug-like'' nNOS inhibitors as a new and promising strategy for the chemoprevention of early melanoma progression and the inhibition of secondary melanoma in high-risk individuals. Conclusion: Based on our observations, we propose that nNOS in melanoma results in constitutive overproduction of NO, which stimulates proliferation and increases invasion potential, leading to subsequent development of metastases.

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Section: Inhibition Of Nnos With Novel Inhibitorsmentioning

confidence: 99%

Targeting Nitric Oxide Signaling with nNOS Inhibitors As a Novel Strategy for the Therapy and Prevention of Human Melanoma

Yang

Misner

et al. 2013

Antioxidants & Redox Signaling

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“…20), is quite polar and may not cross the blood brain barrier (BBB). As a result, Ji et al built on this work by designing nNOS inhibitors with increased lipophilicity and optimized in vivo potency and selectivity [73]. In the GRID [68] analysis of rat nNOS, two hydrophobic areas were identified, one surrounded by Met336, Leu337, Tyr706 and Trp306 in the C1 pocket and another lined by Pro565, Ala566, Val567 and Phe584 in the S pocket (Fig.…”

Section: -Aminopyridine Containing Inhibitorsmentioning

confidence: 99%

“…One such compound is the 2-aminopyridine 15, which has a K i of 0.014 μM molar for rat nNOS inhibition and 2,000 fold selectivity over bovine eNOS and 290 fold over murine iNOS. The 2-aminopyridine 15 was initially tested as mixture of diastereomers [73] (Fig. 21).…”

Section: -Aminopyridine Containing Inhibitorsmentioning

confidence: 99%

“…Over a 20 minute experiment there was little difference between the overall brain concentrations of the tested prodrug analogues of 21. [72] with a secondary amine, and compound 16 [73] with an ester linkage which were used to study how substitution patterns affected passage of nNOS inhibitors across the BBB [105]. The addition of an intramolecular HB is another known strategy used in PK and BBB optimisation of novel inhibitors for a variety of enzymes [107][108][109][110][111].…”

Section: Pharmacokinetics Of Nnos Inhibitorsmentioning

confidence: 99%

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Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

Curtin¹,

Kinsella²,

Stephens

2015

CMC

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Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of biological processes, from vascular pressure to immune responses and neurological signalling cascades. Overproduction of NO has been implicated in conditions including Alzheimer's disease, Parkinson's disease and schizophrenia. Inhibition of nNOS therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These ligands have been targeted at four key binding sites of the nNOS enzyme -the tetrahydrobiopterin, calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the field of nNOS inhibition.

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“…(10), structure-based lead optimization involves the synthesis and biological evaluation of several compounds sharing a high degree of chemical similarity, but still possessing interesting structural diversity. Its success and effectiveness will depend to a large extent on the existence of a well-defined and controlled integration of medicinal chemistry efforts, including molecular modeling, design, synthesis and biological evaluation [10,15,25,39,[89][90][91][92][93][94][95][96][97]]. …”

Section: Structure-based Lead Optimizationmentioning

confidence: 99%

Structure-Based Drug Design Strategies in Medicinal Chemistry

Andricopulo¹,

Salum²,

Abraham

2009

CTMC

138

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A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.Keywords: Structure-based drug design, medicinal chemistry, virtual screening, QSAR, pharmacophores. STRUCTURE-BASED DRUG DESIGNThe performance of biochemical processes and cell mechanisms are dependent upon complex and multiple noncovalent intermolecular interactions between proteins and small-molecule modulators. The understanding of the structural and chemical binding properties of important drug targets in biologically relevant pathways allows the design of small molecules capable of regulating or modulating specific target functions in the body that are closely linked to human diseases and disorders, through multiple intermolecular interactions within a well-defined binding pocket [1][2][3][4]. In general, the identification of promising hits for further optimization is a major challenge faced by the both pharmaceutical and academic laboratories. Although the trial-anderror nature is inherent in drug research, rational concepts and modern computational methods have become widely employed for lead selection and optimization.The use of three-dimensional (3D) protein structure information in the development of new biologically active molecules, which is termed Structure-Based Drug Design (SBDD), is a well-established, successful and highly attarctive strategy used by academic and pharmaceutical research laboratories worldwide [3][4][5][6][7][8]. As a creative and knowledgedriven approach, an essential requirement for structure-based studies is a substantial understanding of the spatial and energetic aspects that affect the binding affinities of proteinligand complexes. Considering that the shape and chemical nature of the binding site of a specific target protein are known, and the possible intermolecular interactions between ligands and the protein within its active site have been identified, this qualified information can be directly employed for the identification of new ligands and the optimization of lead compounds. This opens new possibilities to boost the search for lead molecules and to limit the number of compounds that need to be evaluated experimentally.Hits can be identified through the docking of smallmolecule ligands (selected from databases of chemical structures) into protein active sites or by using receptorbased pharmacophore models. Furthermore, drug candidates can be designed de novo by improving the complementary binding properties of lead compounds and the r...

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Discovery of Highly Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase by Fragment Hopping

Cited by 80 publications

References 67 publications

Targeting Nitric Oxide Signaling with nNOS Inhibitors As a Novel Strategy for the Therapy and Prevention of Human Melanoma

Targeting Nitric Oxide Signaling with nNOS Inhibitors As a Novel Strategy for the Therapy and Prevention of Human Melanoma

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

Structure-Based Drug Design Strategies in Medicinal Chemistry

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