The Discovery of Potentially Selective Human Neuronal Nitric Oxide Synthase (nNOS) Inhibitors: A Combination of Pharmacophore Modelling, CoMFA, Virtual Screening and Molecular Docking Studies

Xu, Guanhong; Chen, Yue; Shen, Kun-Ching; Wang, Xiuzhen; Li, Fēi; He, Yan

doi:10.3390/ijms15058553

Cited by 11 publications

(7 citation statements)

References 41 publications

(39 reference statements)

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“…This strategy can be useful to design novel optimized analogs [58]. Nitric Oxide Synthase -Simple Enzyme-Complex Roles…”

Section: Nitric Oxide Synthase -Simple Enzyme-complex Rolesmentioning

confidence: 99%

Nitric Oxide Synthase Inhibitors

Ferreira¹,

Serafim²

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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Nitric oxide (NO) is an endogenic product from plants, bacteria, and animal cells that has many important effects in those organisms. It is produced by nitric oxide synthase (NOS), which is found in main three isoforms, namely endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). It has an important role in homeostasis in different physiological systems, such as micro-and macro-vascularization, inhibition of platelet aggregation, and neurotransmission regulation in the central nervous, gastrointestinal, respiratory, and genitourinary systems. However, its overproduction has been associated with diseases such as arthritis, asthma, cerebral ischemia, Parkinson's disease, neurodegeneration, and seizures. For this reason, and due to better understanding of the molecular mechanisms by which NO provokes those diseases, the interest on the design of NOS inhibitors with therapeutic purposes has highly increased. Based on the foregoing considerations, the proposal of this chapter is to show an overview about the design strategies, mechanism of action at the molecular level, and the main advances toward the search for selective NOS inhibitors available in the literature.

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“…This strategy can be useful to design novel optimized analogs [58]. Nitric Oxide Synthase -Simple Enzyme-Complex Roles…”

Section: Nitric Oxide Synthase -Simple Enzyme-complex Rolesmentioning

confidence: 99%

Nitric Oxide Synthase Inhibitors

Ferreira¹,

Serafim²

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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“…The generated models were firstly evaluated using the built-in parameters and the top five models of each group were selected based on two criteria: (1) Number of “hits” should be equal or near to the number of active molecules, which in this case was six. (2) Smaller value of Energy and higher value of Specificity were desired for the best model [22]. Thus, 74 active compounds and 222 inactive compounds formed a test set to validate the selected pharmacophore models constructed for three structure types.…”

Section: Resultsmentioning

confidence: 99%

Virtual Screening and Molecular Dynamics Study of Potential Negative Allosteric Modulators of mGluR1 from Chinese Herbs

et al. 2015

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Abstract:The metabotropic glutamate subtype 1 (mGluR1), a member of the metabotropic glutamate receptors, is a therapeutic target for neurological disorders. However, due to the lower subtype selectivity of mGluR1 orthosteric compounds, a new targeted strategy, known as allosteric modulators research, is needed for the treatment of mGluR1-related diseases. Recently, the structure of the seven-transmembrane domain (7TMD) of mGluR1 has been solved, which reveals the binding site of allosteric modulators and provides an opportunity for future subtype-selectivity drug design. In this study, a series of computer-aided drug design methods were utilized to discover potential mGluR1 negative allosteric modulators (NAMs). Pharmacophore models were constructed based on three different structure types of mGluR1 NAMs. After validation using the built-in parameters and test set, the optimal pharmacophore model of each structure type was selected and utilized as a query to screen the Traditional Chinese Medicine Database (TCMD). Then, three different hit lists of compounds were obtained. Molecular docking was used based on the latest crystal structure of mGluR1-7TMD to further filter these hits. As a compound with high QFIT and LibDock Score was preferred, a total of 30 compounds were retained. MD simulation was utilized to confirm the stability of potential compounds binding. From the computational results, OPEN ACCESSMolecules 2015, 20 12770 thesinine-4ʹ-O-β-D-glucoside, nigrolineaxanthone-P and nodakenin might exhibit negative allosteric moderating effects on mGluR1. This paper indicates the applicability of molecular simulation technologies for discovering potential natural mGluR1 NAMs from Chinese herbs.

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“…The approach can be validated initially through the use of theoretical test/validation sets and subsequently through experimental evaluation of the identified compounds. Xu et al [99] performed a tiered virtual screening study incorporating development of a seven feature NOS pharmacophore, a Comparative Molecular Field Analysis (CoMFA) comparison and docking studies using a rat nNOS crystal structure. The pharmacophore model incorporated three hydrophobes, one donor atom, one acceptor atom and two positive nitrogens and was in general agreement with the CoMFA model.…”

Section: Recent Advances In Nnos Inhibitor Design and Optimizationmentioning

confidence: 99%

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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The Discovery of Potentially Selective Human Neuronal Nitric Oxide Synthase (nNOS) Inhibitors: A Combination of Pharmacophore Modelling, CoMFA, Virtual Screening and Molecular Docking Studies

Cited by 11 publications

References 41 publications

Nitric Oxide Synthase Inhibitors

Nitric Oxide Synthase Inhibitors

Virtual Screening and Molecular Dynamics Study of Potential Negative Allosteric Modulators of mGluR1 from Chinese Herbs

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

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