Bioactive Conformation (bioactive + conformation)

Distribution by Scientific Domains


Selected Abstracts


Consistent Bioactive Conformation of the Neu5Ac,(2,3)Gal Epitope Upon Lectin Binding

CHEMBIOCHEM, Issue 18 2008
Anirban Bhunia Dr.
Get to NOE MAG: Partial structures of GQ1b,, the natural ligand of the myelin-associated glycoprotein (MAG), have been synthesized and subjected to NOE experiments to determine their bioactive conformations. The experiments show that the flexible ,(2,3)-glycosidic linkage between N -acetylneuraminic acid and galactose present in all ligands adopts a "sialyl Lewisx -type" binding mode. This information is valuable for the future design of conformationally preorganized MAG inhibitors. [source]


Toward accurate relative energy predictions of the bioactive conformation of drugs

JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 4 2009
Keith T. Butler
Abstract Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol,1 of a local minimum, with penalties above 2.0kcal mol,1 being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery. 2008 Wiley Periodicals, Inc. J Comput Chem 2009 [source]


Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor

JOURNAL OF PEPTIDE SCIENCE, Issue 7 2007
Andreas Axn
Abstract Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C -terminal of angiotensin IV with an o -substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a ,-turn in the C -terminal of its bioactive conformation. Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor. Copyright 2007 European Peptide Society and John Wiley & Sons, Ltd. [source]


Solution structure of nociceptin peptides

JOURNAL OF PEPTIDE SCIENCE, Issue 9 2002
Pietro Amodeo
Abstract Peptides embedded in the sequence of pre-pro-nociceptin, i.e. nociceptin, nocistatin and orphanin FQ2, have shed light on the complexity of the mechanisms involving the peptide hormones related to pain and have opened up new perspectives for the clinical treatment of pain. The design of new ligands with high selectivity and bioavailability, in particular for ORL1, is important both for the elucidation and control of the physiological role of the receptor and for their therapeutic importance. The failure to obtain agonists and antagonists when using, for nociceptin, the same substitutions that are successful for opioids, and the conformational flexibility of them all, justify systematic efforts to study the solution conformation under conditions as close as possible to their natural environment. Structural studies of linear peptides in solution are hampered by their high flexibility. A direct structural study of the complex between a peptide and its receptor would overcome this difficulty, but such a study is not easy since opioid receptors are membrane proteins. Thus, conformational studies of lead peptides in solution are still important for drug design. This review deals with conformational studies of natural pre-nociceptin peptides in several solvents that mimic in part the different environments in which the peptides exert their action. None of the structural investigations yielded a completely reliable bioactive conformation, but the global conformation of the peptides in biomimetic environments can shed light on their interaction with receptors. Copyright 2002 European Peptide Society and John Wiley & Sons, Ltd. [source]


Highly potent side-chain to side-chain cyclized enkephalin analogues containing a carbonyl bridge: synthesis, biology and conformation

JOURNAL OF PEPTIDE SCIENCE, Issue 3 2001
Danuta Pawlak
Abstract Six novel cyclic enkephalin analogues have been synthesized. Cyclization of the linear peptides containing basic amino acid residues in position 2 and 5 was achieved by treatment with bis(4-nitrophenyl)carbonate. It was found that some of the compounds exibit unusually high -opioid activity in the guinea pig ileum (GPI) assay. The 18-membered analogue cyclo(N,,N,, -carbonyl-,,-Lys2,Dap5)enkephalinamide turned out to be one of the most potent -agonists reported so far. NMR spectra of the peptides were recorded and structural parameters were determined. The conformational space was exhaustively examined for each of them using the electrostatically driven Monte Carlo method. Each peptide was finally described as an ensemble of conformations. A model of the bioactive conformation of this class of opioid peptides was proposed. Copyright 2001 European Peptide Society and John Wiley & Sons, Ltd. [source]


A personal account of the role of peptide research in drug discovery: the case of hepatitis C,

JOURNAL OF PEPTIDE SCIENCE, Issue 1 2001
Antonello Pessi
Abstract Although peptides themselves are not usually the end products of a drug discovery effort, peptide research often plays a key role in many aspects of this process. This will be illustrated by reviewing the experience of peptide research carried out at IRBM in the course of our study of hepatitis C virus (HCV). The target of our work is the NS3/4A protease, which is essential for maturation of the viral polyprotein. After a thorough examination of its substrate specificity we fine-tuned several substrate-derived peptides for enzymology studies, high-throughput screening and as fluorescent probes for secondary binding assays. In the course of these studies we made the key observation: that the protease is inhibited by its own cleavage products. Single analog and combinatorial optimization then derived potent peptide inhibitors. The crucial role of the NS4A cofactor was also addressed. NS4A is a small transmembrane protein, whose central domain is the minimal region sufficient for enzyme activation. Structural studies were performed with a peptide corresponding to the minimal activation domain, with a series of product inhibitors and with both. We found that NS3/4A is an induced fit enzyme, requiring both the cofactor and the substrate to acquire its bioactive conformation; this explained some puzzling results of ,serine-trap' type inhibitors. A more complete study on NS3 activation, however, requires the availability of the full-length NS4A protein. This was prepared by native chemical ligation, after sequence engineering to enhance its solubility; structural studies are in progress. Current work is focused on the P, region of the substrate, which, at variance with the P region, is not used for ground state binding to the enzyme and might give rise to inhibitors showing novel interactions with the enzyme. Copyright 2001 European Peptide Society and John Wiley & Sons, Ltd. [source]


The refolding of different ,-fetoprotein variants

PROTEIN SCIENCE, Issue 9 2006
Susanna S.J. Leong
Abstract The effect of glycosylation on AFP foldability was investigated by parallel quantitative and qualitative analyses of the refolding of glycosylated and nonglycosylated AFP variants. Both variants were successfully refolded by dialysis from the denatured-reduced state, attaining comparable "refolded peak" profiles and refolding yields as determined by reversed-phase HPLC analysis. Both refolded variants also showed comparable spectroscopic fingerprints to each other and to their native counterparts, as determined by circular dichroism spectroscopy. Inclusion body-derived AFP was also readily refolded via dilution under the same redox conditions as dialysis refolding, showing comparable circular dichroism fingerprints as native nonglycosylated AFP. Quantitative analyses of inclusion body-derived AFP showed sensitivity of AFP aggregation to proteinaceous and nonproteinaceous inclusion body contaminants, where refolding yields increased with increasing AFP purity. All of the refolded AFP variants showed positive responses in ELISA that corresponded with the attainment of a bioactive conformation. Contrary to previous reports that the denaturation of cord serum AFP is an irreversible process, these results clearly show the reversibility of AFP denaturation when refolded under a redox-controlled environment, which promotes correct oxidative disulfide shuffling. The successful refolding of inclusion body-derived AFP suggests that fatty acid binding may not be required for the attainment of a rigid AFP tertiary structure, contrary to earlier studies. The overall results from this work demonstrate that foldability of the AFP molecule from its denatured-reduced state is independent of its starting source, the presence or absence of glycosylation and fatty acids, and the refolding method used (dialysis or dilution). [source]


Cover Picture: A Cyclic CCK8 Analogue Selective for the Cholecystokinin Type A Receptor: Design, Synthesis, NMR Structure and Binding Measurements (ChemBioChem 11/2003)

CHEMBIOCHEM, Issue 11 2003
Stefania De Luca Dr.
Abstract The cover picture shows a molecular model of the interaction between the new CCK8 analogue, Cycle29,34[Dpr29,Lys34]-CCK8 (shown as a CPK model) and the receptor fragment CCKA -R(1,47) (represented by a pink ribbon). The introduction of the cyclic constraint between the Dpr29 sidechain and the CCK8 C terminus (Lys34) decreases the flexibility of the molecule to stabilize the bioactive conformation of Cycle29,34[Dpr29,Lys34]-CCK8. The Trp30 and Met31 side chains are in favorable orientations for interaction with the CCKA receptor. Expansions of the aromatic/amide regions of the 1H NMR spectra of Cycle29,34[Dpr29,Lys34]-CCK8 in aqueous solution (top) and in presence of dodecylphosphocholine-d38 micelles (bottom) are shown in the inset. Further details can be found in the article by Morelli and co-workers on p. 1176 ff. [source]


Structure,Activity Study on the Spatial Arrangement of the Third Aromatic Ring of Endomorphins 1 and 2 Using an Atypical Constrained C,Terminus

CHEMMEDCHEM, Issue 3 2007
Ye Yu Dr.
Abstract The discovery of endomorphins (EMs) has opened the possibility of searching for new analgesics. However, the design of peptide analgesics has proven to be very difficult as a result of their conformational flexibility and a lack of clarity in structure,activity relationships (SAR). In EMs, the amino acid side chains exhibit considerable conformational flexibility, especially in the third aromatic ring, which is free to adopt a bioactive conformation. To resolve these problems, a series of C,terminus EM analogues, [Xaa4 -R]EMs, modified through the substitution of Phe4 with nonaromatic residues and termination with benzyl groups, were designed to generate conformational constrains of the third aromatic ring by amide bond and torsion angles (,4 and ,4) of Xaa4. Introduction of (S)-,-methyl or (S)/(R)-,-carboxamide on the methylene unit of the benzyl group was designed to produce an atypical topographical constraint (,5) of the third aromatic ring rotation. Interestingly, some EM derivatives, with elimination of the C-terminal carboxamide group and significant changes in the address sequence (Phe4 -NH2), still exhibited higher ,-opioid receptor (MOR) affinity than unmodified EMs. In contrast, some analogues with incorrectly constrained C,termini displayed very low affinity and pharmacological activities. Thus, our results indicate that these EM analogues, with atypical constrained C,termini, provide model compounds with potent MOR agonism. They also give evidence that the proper spatial orientation and conformational restriction of the third aromatic ring are crucial for the interaction of EMs with MOR. [source]


Toward accurate relative energy predictions of the bioactive conformation of drugs

JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 4 2009
Keith T. Butler
Abstract Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol,1 of a local minimum, with penalties above 2.0kcal mol,1 being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery. 2008 Wiley Periodicals, Inc. J Comput Chem 2009 [source]


Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG-CoA reductase

JOURNAL OF MOLECULAR RECOGNITION, Issue 4 2008
Valeriy V. Pak
Abstract This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion ("V" parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC50,=,0.4,M) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC50,=,484,M) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides. Copyright 2008 John Wiley & Sons, Ltd. [source]


Consistent Bioactive Conformation of the Neu5Ac,(2,3)Gal Epitope Upon Lectin Binding

CHEMBIOCHEM, Issue 18 2008
Anirban Bhunia Dr.
Get to NOE MAG: Partial structures of GQ1b,, the natural ligand of the myelin-associated glycoprotein (MAG), have been synthesized and subjected to NOE experiments to determine their bioactive conformations. The experiments show that the flexible ,(2,3)-glycosidic linkage between N -acetylneuraminic acid and galactose present in all ligands adopts a "sialyl Lewisx -type" binding mode. This information is valuable for the future design of conformationally preorganized MAG inhibitors. [source]