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Receptor Binding Affinity (receptor + binding_affinity)
Selected AbstractsClassical QSAR Modeling of CCR5 Receptor Binding Affinity of Substituted BenzylpyrazolesMOLECULAR INFORMATICS, Issue 6 2004Thomas Leonard Abstract CCR5 receptor binding affinity of a series of substituted benzylpyrazole derivatives was subjected to QSAR study using Fujita-Ban type analysis and a mixed approach based on Hansch and Fujita-Ban analyses. Apart from appropriate indicator variables encoding different group contributions, different physicochemical variables like hydrophobicity (,), electronic (Hammett ,) and steric (molar refractivity, STERIMOL values) parameters of phenyl ring substituents of the benzyl moiety of the compounds were used as predictor variables. Additionally, Wang-Ford charges of the common atoms of the compounds calculated from molecular electrostatic potential surface of AM1 optimized geometries of the compounds and various topological parameters were used as additional descriptors. The variables for the multiple regression analyses were selected based on principal component factor analysis and generated equations were statistically validated using leave-one-out technique and predicting the binding affinities of test set compounds. The analysis explores the substitutional requirements of the phenyl nucleus of the benzylpyrazole moiety of the compounds for effective binding with CCR5 receptor. [source] The effects of a progesterone metabolite, 5,-dihydroprogesterone, on oxytocin receptor binding in human myometrial membranesBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 6 2003Shirley Astle Objective To determine the effect of the progesterone metabolite 5,-dihydroprogesterone on human oxytocin receptor binding in myometrial membranes and on whole-cell calcium current in single myometrial cells. Design Receptor binding studies in human myometrial membranes prepared from biopsies taken before or after the onset of labour and in Chinese hamster ovary cells expressing the human oxytocin receptor. Whole cell patch-clamp experiments were undertaken on isolated myometrial cells. Setting University research laboratories and University hospital. Population Patients undergoing caesarean section at term either prior to or following onset of labour. Methods Myometrial biopsies were taken from women undergoing caesarean section. The binding affinities of oxytocin, 5,-dihydroprogesterone and atosiban were determined in myometrial membranes and Chinese hamster ovary cells expressing the human oxytocin receptor. The effect of 5,-dihydroprogesterone on inward current was also determined in isolated myometrial cells. Main outcome measures Receptor binding affinity and electrophysiological inward current. Results 5,-Dihydroprogesterone did not reduce oxytocin receptor binding in myometrial membranes or Chinese hamster ovary cells expressing the human oxytocin receptor. Nor did it influence calcium current under whole-cell patch conditions in single myometrial cells. In contrast, atosiban inhibited binding in myometrial membranes prepared from samples taken either prior to or following labour (Ki= 112 and 108 nM, respectively). The affinity of atosiban for the oxytocin receptor was much lower than oxytocin (Ki= 5 and 6 nM in samples taken before or after labour, respectively) in myometrial membranes and in Chinese hamster ovary cells expressing the human oxytocin receptor (Ki= 63 M and 1 nM for atosiban and oxytocin, respectively). Conclusions We conclude that 5,-dihydroprogesterone is unlikely to regulate myometrial activity as a result of a direct effect on oxytocin receptor binding or inward calcium current. [source] Parsing the Effects of Binding, Signaling, and Trafficking on the Mitogenic Potencies of Granulocyte Colony-Stimulating Factor AnaloguesBIOTECHNOLOGY PROGRESS, Issue 3 2003Casim A. Sarkar The pharmacodynamic potency of a therapeutic cytokine interacting with a cell-surface receptor can be attributed primarily to three central properties: [1] cytokine/receptor binding affinity, [2] cytokine/receptor endocytic trafficking dynamics, and [3] cytokine/receptor signaling. Thus, engineering novel or second-generation cytokines requires an understanding of the contribution of each of these to the overall cell response. We describe here an efficient method toward this goal in demonstrated application to the clinically important cytokine granulocyte colony-stimulating factor (GCSF) with a chemical analogue and a number of genetic mutants. Using a combination of simple receptor-binding and dose-response proliferation assays we construct an appropriately scaled plot of relative mitogenic potency versus ligand concentration normalized by binding affinity. Analysis of binding and proliferation data in this manner conveniently indicates which of the cytokine properties,binding, trafficking, and/or signaling,are contributing substantially to altered potency effects. For the GCSF analogues studied here, two point mutations as well as a poly(ethylene glycol) chemical conjugate were found to have increased potencies despite comparable or slightly lower affinities, and trafficking was predicted to be the responsible mechanism. A third point mutant exhibiting comparable binding affinity but reduced potency was predicted to have largely unchanged trafficking properties. Surprisingly, another mutant possessing an order-of-magnitude weaker binding affinity displayed enhanced potency, and increased ligand half-life was predicted to be responsible for this net beneficial effect. Each of these predictions was successfully demonstrated by subsequent measurements of depletion of these five analogues from cell culture medium. Thus, for the GCSF system we find that ligand trafficking dynamics can play a major role in regulating mitogenic potency. Our results demonstrate that cytokine analogues can exhibit pharmacodynamic behaviors across a diverse spectrum of "binding-potency space" and that our analysis through normalization can efficiently elucidate hypotheses for the underlying mechanisms for further dedicated testing. We have also extended the Black-Leff model of pharmacological agonism to include trafficking effects along with binding and signaling, and this model provides a framework for parsing the effects of these factors on pharmacodynamic potency. [source] Conformational studies of novel estrogen receptor ligands by 1D and 2D NMR spectroscopy and computational methodsMAGNETIC RESONANCE IN CHEMISTRY, Issue 4 2003Albert B. Sebag Abstract The solution conformations of the novel estrogen receptor ligands (17,,20E)-(p -trifluoromethylphenyl)vinylestradiol (1) and (17,,20E)-(o -trifluoromethylphenyl)vinylestradiol (2) were investigated in 2D and 1D NOESY studies and by comparison of 13C NMR chemical shifts with theoretical shieldings. The 1H and 13C assignments of 1 and 2 were determined by DEPT, COSY and HMQC experiments. The conformations of the 17,-phenylvinyl substituents of 1 and 2 are of interest because of their differing receptor binding affinities and effects in in vivo uterotrophic growth assays. A statistical method of evaluating contributing conformers of 1 and 2 from predicted 13C shifts of possible structures correlated fairly well with conformational conclusions derived from the NOE data. The 17, substituents of 1 and 2 apparently exist in similar conformational equilibria, suggesting that while 1 and 2 would occupy a similar receptor volume, interactions with the protein may shift the equilibrium and thereby influence the expression of the ligand. Copyright © 2003 John Wiley & Sons, Ltd. [source] Bioisosterism, enantioselectivity, and molecular modeling of new effective N6 - and/or N(9)-substituted 2-phenyl adenines and 8-aza analogs: Different binding modes to A1 adenosine receptorsDRUG DEVELOPMENT RESEARCH, Issue 2 2001A. Maria Bianucci Abstract Bioisosterism of the adenine and 8-azaadenine nuclei was demonstrated by comparison of A1 adenosine receptor binding affinity of 2-phenyl N6 -substituted adenines and the corresponding 8-azaadenines. Some of these new compounds are very potent A1 adenosine receptor antagonists. This work also describes the synthesis and A1 adenosine receptor binding of the enantiomers of some 2-phenyladenines substituted with a 1-phenylethyl chiral group in N6 and N(9) positions. Biological results, showing the same stereoselectivity for all the couples of enantiomers, may supply proof for the hypothesis of a possible double arrangement of 2-phenylsubstituted adenines inside A1 adenosine receptors. Theoretical studies, based on an improved A1 adenosine receptor model and consisting of evaluation and comparison of interaction energies in complexes involving some selected chiral ligands, support the above hypothesis. Drug Dev. Res. 54:52,65, 2001. © 2001 Wiley-Liss, Inc. [source] Current trends in the structure,activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonistMEDICINAL RESEARCH REVIEWS, Issue 5 2005Andrzej M. Wilczynski Abstract Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-3 and -4 (MC3R and MC4) G-protein coupled receptors. The 87,132 amino acid C-terminal domain of hAGRP possesses five disulfide bridges and a well-defined three-dimensional structure that displays full biological activity as compared to the full-length protein. Based on the NMR structure of the C-terminal AGRP(87,132), a novel mini-protein, referred to as "Mini-AGRP" was designed that exhibited receptor binding affinity and antagonism similar to that of the parent hAGRP(87,132) protein. It was demonstrated that this new-engineered protein autonomously folds to the inhibitor cystine knot (ICK) motif. As this AGRP is a novel mammalian protein involved in energy homeostasis and possibly other physiological functions remaining to be identified, structure-function studies are starting to emerge toward the understanding of how this unique protein putatively interacts with the melanocortin receptors with the objective of designing potential therapeutic agents for in vivo physiological studies. This article summarizes the progress to date of AGRP-based structure,activity relationships and putative ligand,receptor interactions. © 2005 Wiley Periodicals, Inc. [source] Classical QSAR Modeling of CCR5 Receptor Binding Affinity of Substituted BenzylpyrazolesMOLECULAR INFORMATICS, Issue 6 2004Thomas Leonard Abstract CCR5 receptor binding affinity of a series of substituted benzylpyrazole derivatives was subjected to QSAR study using Fujita-Ban type analysis and a mixed approach based on Hansch and Fujita-Ban analyses. Apart from appropriate indicator variables encoding different group contributions, different physicochemical variables like hydrophobicity (,), electronic (Hammett ,) and steric (molar refractivity, STERIMOL values) parameters of phenyl ring substituents of the benzyl moiety of the compounds were used as predictor variables. Additionally, Wang-Ford charges of the common atoms of the compounds calculated from molecular electrostatic potential surface of AM1 optimized geometries of the compounds and various topological parameters were used as additional descriptors. The variables for the multiple regression analyses were selected based on principal component factor analysis and generated equations were statistically validated using leave-one-out technique and predicting the binding affinities of test set compounds. The analysis explores the substitutional requirements of the phenyl nucleus of the benzylpyrazole moiety of the compounds for effective binding with CCR5 receptor. [source] Potent Opioid Peptide Agonists Containing 4,-[N -((4,-phenyl)-phenethyl)carboxamido]phenylalanine (Bcp) in Place of TyrCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2008Grazyna Weltrowska Analogues of the opioid peptides H-Tyr-c[d -Cys-Gly-Phe(pNO2)- d -Cys]NH2 (non-selective), H-Tyr- d -Arg-Phe-Lys-NH2 (,-selective) and dynorphin A(1-11)-NH2 (,-selective) containing 4,-[N -((4,-phenyl)-phenethyl)carboxamido]phenylanine (Bcp) in place of Tyr1 were synthesized. All three Bcp1 -opioid peptides retained high , opioid receptor binding affinity, but showed very significant differences in the opioid receptor selectivity profiles as compared with the corresponding Tyr1 -containing parent peptides. The cyclic peptide H-Bcp-c[d -Cys-Gly-Phe(pNO2)- d -Cys]NH2 turned out to be an extraordinarily potent, ,-selective opioid agonist, whereas the Bcp1 -analogue of dynorphin A(1-11)-NH2 displayed partial agonism at the , receptor. The obtained results suggest that the large biphenylethyl substituent contained in these compounds may engage in a hydrophobic interaction with a receptor subsite and thereby may play a role in the ligand's ability to induce a specific receptor conformation or to bind to a distinct receptor conformation in a situation of conformational receptor heterogeneity. [source] | ||||||||||||||||