Struct - a triangulation algorithm to visualize molecular quantities

Brickmann, Jürgen; Bertling, H; Russian, B M; Knoblauch, Martin; Waldherr-Teschner, Michael

doi:10.1016/0263-7855(86)80069-8

Cited by 3 publications

(3 citation statements)

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“…Figure shows the binding mode for PHS 334 using QXP in comparison to the experimental binding mode of H 4 Bip in the rat NOS-I X-ray structure. Hydrogens are omitted for clarity; the protein binding pocket is indicated using a solvent-accessible surface , colored by cavity depth. , Since the Monte Carlo based docking could reproduce H 4 Bip orientation only with structural water molecules, these were further included. The postulated binding mode of PHS 334 is similar in both human and rat NOS-I cavities and agrees with that of H 4 Bip with direct and potentially water-mediated interactions to heme propionic acid side chain.…”

Section: Resultsmentioning

confidence: 99%

Structural Analysis of Isoform-Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases

et al. 2005

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Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I-III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are of clinical interest, given their differing pathophysiological roles. Here we describe our approach to target the unique NOS (6R,1'R,2'S)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) binding site. By a combination of ligand- and structure-based design, the structure-activity relationship (SAR) for a focused set of 41 pteridine analogues on four scaffolds was developed, revealing selective NOS-I inhibitors. The X-ray crystal structure of rat NOS-I dimeric-oxygenase domain with H(4)Bip and l-arginine was determined and used for human isoform homology modeling. All available NOS structural information was subjected to comparative analysis of favorable protein-ligand interactions using the GRID/concensus principal component analysis (CPCA) approach to identify the isoform-specific interaction site. Our interpretation, based on protein structures, is in good agreement with the ligand SAR and thus permits the rational design of next-generation inhibitors targeting the H(4)Bip binding site with enhanced isoform selectivity for therapeutics in pathology with NO overproduction.

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Section: Resultsmentioning

confidence: 99%

Structural Analysis of Isoform-Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases

et al. 2005

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“…The program MOLCAD was used to visualize protein−ligand interactions by mapping properties such as lipophilicity , and electrostatic potential (obtained using the Poisson−Boltzmann equation) onto solvent accessible surfaces . The step width for the grid to compute the Poisson−Boltzmann electrostatic potential was set to 1 Å, while the border width of the solvent grid around the molecule was set to 8 Å. Dielectric constants of 80 for the solvent and 2 for the solute were used.…”

Section: Methodsmentioning

confidence: 99%

Structural Requirements for Inhibition of the Neuronal Nitric Oxide Synthase (NOS-I): 3D-QSAR Analysis of 4-Oxo- and 4-Amino-Pteridine-Based Inhibitors

Matter¹,

Kotsonis

Klingler

et al. 2002

J. Med. Chem.

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The family of homodimeric nitric oxide synthases (NOS I-III) catalyzes the generation of the cellular messenger nitric oxide (NO) by oxidation of the substrate L-arginine. The rational design of specific NOS inhibitors is of therapeutic interest in regulating pathological NO levels associated with sepsis, inflammatory, and neurodegenerative diseases. The cofactor (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) maximally activates all NOSs and stabilizes enzyme quaternary structure by promoting and stabilizing dimerization. Here, we describe the synthesis and three-dimensional (3D) quantitative structure-activity relationship (QSAR) analysis of 65 novel 4-amino- and 4-oxo-pteridines (antipterins) as inhibitors targeting the H(4)Bip binding site of the neuronal NOS isoform (NOS-I). The experimental binding modes for two inhibitors complexed with the related endothelial NO synthase (NOS-III) reveal requirements of biological affinity and form the basis for ligand alignment. Different alignment rules were derived by building other compounds accordingly using manual superposition or a genetic algorithm for flexible superposition. Those alignments led to 3D-QSAR models (comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)), which were validated using leave-one-out cross-validation, multiple analyses with two and five randomly chosen cross-validation groups, perturbation of biological activities by randomization or progressive scrambling, and external prediction. An iterative realignment procedure based on rigid field fit was used to improve the consistency of the resulting partial least squares models. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which correspond to experimentally determined NOS-II and -III H(4)Bip binding site topologies as well as to the NOS-I homology model binding site in terms of steric, electrostatic, and hydrophobic complementarity. These models provide clear guidelines and accurate activity predictions for novel NOS-I inhibitors.

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“…1), a graphical presentation of the mean surface can be performed on a graphical workstation, using the program package MOLCAD [23]. The standard deviation of each surface dot is projected onto the molecular surface in different colours.…”

Section: Methods Of Calculationmentioning

confidence: 99%

Surface comparisons of some odour molecules: Conformational calculations on sandalwood odour V

Buchbauer

Winiwarter

Wolschann

1992

J Computer-Aided Mol Des

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Struct - a triangulation algorithm to visualize molecular quantities

Cited by 3 publications

References 0 publications

Structural Analysis of Isoform-Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases

Structural Analysis of Isoform-Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases

Structural Requirements for Inhibition of the Neuronal Nitric Oxide Synthase (NOS-I): 3D-QSAR Analysis of 4-Oxo- and 4-Amino-Pteridine-Based Inhibitors

Surface comparisons of some odour molecules: Conformational calculations on sandalwood odour V

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