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N el Tayar

Publications and source records attributed to N el Tayar.

At least 19 recordsLinked to original sources
PubMed1996

Advances in the molecular understanding of gonadotropins-receptors interactions.

The extracellular domain (ECD) of gonadotropin receptors belong to the leucine-rich repeat (LRR) protein superfamily and their transmembrane domain (TMD) is characteristic of the seven alpha-helices G-protein-coupled receptors (GPCR). The availability of the X-ray structures of porcine ribonuclease inhibitor (RI), a LRR protein, and bacteriorhodopsin (bR) allows the construction of 3D models of the ECD and the TMD of gonadotropin receptors, respectively. The predicted models are to a large extent consistent with currently available biochemical and mutational data. The models provide a reliable basis for understanding how the hormone binds and activates its receptor. The ECD, in particular the LRR region, serves as a baseball glove which efficiently catches the large hormone and optimally orient the appropriate parts of it for interaction with the seven-transmembrane-helix domain of the receptor. This in turn is expected to lead to a conformational change to be sensed by the appropriate G-protein complex leading to the stimulation of cAMP synthesis and steroids production.

Binding Sites↗
PubMed1995

Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions.

BACKGROUND: Glycoprotein hormones influence the development and function of the ovary, testis and thyroid by binding to specific high-affinity receptors. The extracellular domains of these receptors are members of the leucine-rich repeat (LRR) protein superfamily and are responsible for the high-affinity binding. The crystal structure of a glycoprotein hormone, namely human choriogonadotropin (hCG), is known, but neither the receptor structure, mode of hormone binding, nor mechanism for activation, have been established. RESULTS: Despite very low sequence similarity between exon-demarcated LRRs in the receptors and the LRRs of porcine ribonuclease inhibitor (RI), the secondary structures for the two repeat sets are found to be alike Constraints on curvature and beta-barrel geometry from the sequence pattern for repeated beta alpha units suggest that the receptors contain three-dimensional structures similar to that of RI. With the RI crystal structure as a template, models were constructed for exons 2-8 of the receptors. The model for this portion of the choriogonadotropin receptor is complementary in shape and electrostatic characteristics to the surface of hCG at an identified focus of hormone-receptor interaction. CONCLUSIONS: The predicted models for the structures and mode of hormone binding of the glycoprotein hormone receptors are to a large extent consistent with currently available biochemical and mutational data. Repeated sequences in beta-barrel proteins are shown to have general implications for constraints on structure. Averaging techniques used here to recognize the structural motif in these receptors should also apply to other proteins with repeated sequences.

Amino Acid Sequence↗
PubMed1993

Solvent-dependent conformation and hydrogen-bonding capacity of cyclosporin A: evidence from partition coefficients and molecular dynamics simulations.

The partition coefficient of cyclosporin A (CsA) was measured in octanol/water and heptane/water by centrifugal partition chromatography. By comparison with results from model compounds, it was deduced that the hydrogen-bonding capacity of CsA changed dramatically from an apolar solvent (where it is internally H-bonded) to polar solvents (where it exposes its H-bonding groups to the solvent). Molecular dynamics simulations in water and CCl4 support the suggestion that CsA undergoes a solvent-dependent conformational changes and that the interconversion process is slow on the molecular dynamics time scale.

Amino Acid Isomerases↗
PubMed1993

Effects of solvation on the ionization and conformation of raclopride and other antidopaminergic 6-methoxysalicylamides: insight into the pharmacophore.

Previous work has shown that raclopride in water at neutral pH exists in a zwitterionic form, suggesting a stereoelectronic structure largely different from that of other benzamides. In the present study, the acid-base behavior of other 6-methoxysalicylamides is shown to be comparable to that of raclopride. An extensive investigation by high-temperature molecular dynamics gave insight into the conformational behavior of neutral and zwitterionic raclopride in vacuum and in water. Partitioning of raclopride and a more rigid analogue with characterization (by first-derivative UV spectroscopy) of the predominant forms in the organic phase indicated that only neutral, internally H-bonded forms partition into the organic solvent. Thus, the predominant forms of 6-methoxysalicylamides will be very different in the aqueous and organic phases. In the latter phase, and hence presumably also in the receptor phase, the drugs exist with a neutral, internally H-bonded phenolic group and are therefore stereoelectronically similar to other substituted benzamides.

Dopamine D2 Receptor Antagonists↗
PubMed1991

Partitioning of solutes in different solvent systems: the contribution of hydrogen-bonding capacity and polarity.

Published partition coefficient values of 121 solutes in five solvent systems (1-octanol-water, n-heptane-water, chloroform-water, diethyl ether-water, and n-butyl acetate-water) were correlated with solute properties, namely intrinsic molecular volume (indicator of cavity formation) and the solvatochromic parameters pi* (dipolarity/polarizability), beta (H-bond acceptor basicity), and alpha (H-bond donor acidity). While the cavity term and the H-bond accepting capacity played a comparable role in all solvent systems, the H-bond donor acidity was significant only in the alkane-water and chloroform-water systems. Comparison of the regression coefficients of pi*, beta, and alpha demonstrated the important role that water content at saturation in the organic solvents plays in the partitioning of solutes. Analysis of the differences between 1-octanol-water and n-heptane-water partition coefficients (delta log Poct-hep) and between 1-octanol-water and chloroform-water partition coefficients (delta log Poct-chf) showed that these values mainly quantitate the capacity of solute to donate hydrogen bonds. In contrast, the differences between 1-octanol-water and diethyl ether-water or n-butylacetate-water partition coefficients, (delta log Poct-dee and delta log Poct-ba, respectively) contain no structural information.

Chemical Phenomena↗
PubMed1991

Percutaneous penetration of drugs: a quantitative structure-permeability relationship study.

Human skin permeation data taken from the literature were analyzed for quantitative relationships with physicochemical properties and structural descriptors. No correlations exist with molecular weights and solvent-accessible surface areas. In most cases, skin permeation was inversely correlated with the parameter delta log Poct-hep (i.e., log Poctanol minus log Pheptane), which is mainly a measure of the H-bond donor acidity of the solutes. Lipophilicity itself, as expressed by log Poctanol, also contributes positively to skin permeation in some cases. The results of this quantitative structure-permeability relationship study are interpreted in terms of a unified mechanistic model whereby drugs can permeate via an intercellular route (correlation with both delta log Poct-hep and log Poct) and/or a transcellular route (correlation with log Poct only).

Administration, Topical↗
PubMed1991

Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity.

Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membranes.

Calorimetry↗
PubMed1991

Determination of lipophilicity and hydrogen-bond donor acidity of bioactive sulphonyl-containing compounds by reversed-phase HPLC and centrifugal partition chromatography and their application to structure-activity relations.

The lipophilic character of two large series of substituted benzenesulphonamides (BzSA) and 4-aminodiphenylsulphones (4-ADS) has been assessed by two chromatographic methods, i.e. reversed-phase HPLC using a relatively novel octadecylpolyvinyl packing and centrifugal counter-current chromatography (CPC). The octadecylpolyvinyl stationary phase proved an interesting alternative to the more common octadecylsilane type stationary phase for obtaining retention parameters correlated to partition coefficients (i.e. log P). The CPC method, being far less time-consuming and markedly more precise than the classical shake-flask method, offers a promising alternative for measuring partition coefficients. The parameter delta log Poct-hep, i.e. log Poctanol minus log Pheptane, was also determined for both congeneric series and was indicative of a similar H-bonding capacity for the SO2NH2 and 4-NH2-C6H4-SO2 groups. QSAR analyses of carbonic anhydrase inhibition by BzSA and antimycobacterial activity of 4-ADS show the capacity of the new lipophilicity parameters to express the hydrophobic component of the drug-enzyme interactions and to reveal a possible role of H-bond donor capacity in governing the antimycobacterial activity of 4-ADS.

Carbonic Anhydrase Inhibitors↗
PubMed1990

Toxication of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and analogs by monoamine oxidase. A structure-reactivity relationship study.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits motor deficits similar to those observed in Parkinson's disease. Before exerting its neurotoxic action, MPTP must be activated by brain monoamine oxidase (MAO) to the neurotoxic metabolite MPP+ (1-methyl-4-phenylpyridinium). MPTP derivatives differ in their reactivity as MAO substrates and in their neurotoxicity. A structure-reactivity relationship study based on literature data was undertaken in order to determine the key features in the structure of MPTP and analogs that are responsible for the reactivity towards MAO. Thirty-three MPTP derivatives (including MPTP itself) were included in the study. To explain the reactivity towards MAO of the 33 MPTP analogs, different statistical methods (principal component analysis, multiple linear regression analysis) as well as the CoMFA (Comparative Molecular Field Analysis) approach, a new tool in structure-activity correlations, were used. Linear regression analysis failed to yield any predictive model, but suggested some trends. In contrast, the CoMFA approach was successful in correlating structural features and MAO reactivity. Coefficient contour maps showed where differences in the steric field (van der Waals' interactions) are most highly associated with differences in MAO reactivity. Several positive (in the ortho- and meta-position of the phenyl group) and negative (in the para-position of the phenyl group; beyond the N-methyl group) interaction regions were identified. Some structural features of the MAO active site could be postulated. First, the N-methyl group has the ideal size and elicits ideal interactions within the MAO active pocket, while smaller or larger groups are less favorable; second, para-substituent on the phenyl ring produce steric hindrances and are unfavorable to reactivity; third, ortho- and meta-substituents may have stabilizing interactions within the active pocket and are favorable to the reactivity. Moreover the model derived by CoMFA allowed us to make successful predictions of reactivity towards MAO for several additional tetrahydropyridines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Pattern recognition study of QSAR substituent descriptors.

Parameter values for 59 common substituents and 74 descriptors used in QSAR studies were compiled. This data matrix was analysed by a variety of multivariate techniques. Linear regression confirmed that lipophilicity can be factorized into two terms, one related to molecular bulk and the other to polarity. Principal component analysis (PCA) of parameters revealed 5 significant principal components and a grouping of lipophilic, steric and electronic parameters. The different loadings of parameters with 5 PCA were also explored. The classification of substituents by cluster analysis (CA) proved rather disappointing. In contrast, the SIMCA method classified substituents of increasing bulk into 5 groups of increasing polarity.

Analysis of Variance↗
PubMed1988

Modeling of beta-adrenoceptors based on molecular electrostatic potential studies of agonists and antagonists.

The molecular electrostatic potential (MEP) of 32 beta-adrenoceptor ligands, mainly antagonists, was calculated by the STO-3G ab initio quantum mechanical method. The MEP of phenylethanolamines (PEAs) features a negative minimum in the meta region (designated M1) which is topographically equivalent to a minimum (designated M2) found in the vicinity of the aromatic ring in all (aryloxy)propanolamines (AOPAs). In these compounds, a second negative zone located beyond the meta position and designated M3 is found in all beta 1-selective antagonists and in some nonselective and beta 2-selective antagonists. The beta 1-selective antagonists feature in the para position an additional zone which is positive (P4) in the full antagonists and negative (M4) in the antagonists displaying intrinsic sympathomimetic activity (ISA). The MEP-based pharmacophoric models of PEAs, AOPAs, and oxime ethers show common elements and lead to a proposed general model for beta-adrenoceptor ligands.

Adrenergic beta-Agonists↗