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At least 829 records · Page 46Linked to original sources
PubMed1986

Conformational analysis of clinically active anticonvulsant drugs.

A series of ureides active against grand mal epilepsy have been studied by using classical potential energy calculations. The series includes phenyl ethyl and diphenyl derivatives of hydantoins, succinimides, glutarimides, oxazolidine-2,4-diones, pyrimidine-2,6-diones, barbituric acids, and phenacemide. A thorough examination of the conformational possibilities did not reveal an exclusive conformation that could account for their activity. However, comparisons with diazepam and other benzodiazepines known to have the ability to competitively bind with drugs such as diphenylhydantoin at some sites show that there is a distinct conformational preference that may well account for their activity against grand mal epilepsy. The conformational studies led to the proposal of a general model for anticonvulsant activity comprising two aromatic rings or their equivalent in a favored orientation and a third region, usually a cyclic ureide, comprising a number of hydrogen-bond-forming functional groups. The specific placement of hydrogen-bonding groups in this region appears to be of less importance than the correct conformational arrangement of the hydrophobic elements.

Anticonvulsants↗
PubMed2002

Synthesis and conformational analysis of small peptides containing 6-endo-BT(t)L scaffolds as reverse turn mimetics.

Two new dipeptide isosteres derived from L-leucine and meso-tartaric acid derivatives, named 6-endo-BTL and 6-endo-BtL, were inserted in a small peptide by means of SPPS, and the conformational features of the resulting peptides 3 and 4 were studied by NMR, IR, and molecular modeling techniques. The presence of a reverse turn conformation was observed in all the structures, suggesting the key role of the scaffolds as reverse turn promoters. Peptides 3 and 4 did not adopt a preferred conformation as indicated by the presence of equilibria between open turn and intramolecular hydrogen-bonded structures. 6-endo-BTL-peptide 3 showed a 3:1 mixture of conformers. The major conformer adopted mainly an open turn structure in equilibrium with hydrogen-bonded structures. The minor conformer displayed a better organized structure with a 14-membered ring hydrogen-bond typical of a beta-hairpin-like structure, in equilibrium with a gamma-turn, too. 6-endo-BtL-peptide 4 showed a unique conformer, and did not adopt as good a conformation as 3, due to the bulky equatorial substituent at C-2. Thus, marked structural differences between peptides containing 6-endo-BTL and 6-endo-BtL scaffolds as reverse turn inducers exist.

Amino Acid Sequence↗
PubMed1993

Conformational analysis of the type II and type III collagen alpha-1 chain C-telopeptides by 1H NMR and circular dichroism spectroscopy.

The type II and type III collagen alpha-1 chain C-telopeptides are a 27 mer with the sequence NAc-GPGIDMSAFAGLGPREKGPDPLQYMRA and a 22mer,NAc-GGGVASLGAGEKGPVGYGYEYR, respectively. Their conformations have been studied in CD3OH/H2O (80/20) solution by means of two-dimensional proton NMR and CD spectroscopy. Based on TOCSY and NOESY experiments, all resonances were assigned and the conformational properties were analyzed in terms of vicinal NH-H alpha coupling constants, sequential and medium range NOEs and amide proton temperature coefficients. The conformation of the type II C-telopeptide is essentially extended. Evidence from CD spectroscopy suggests that a very minor proportion of the peptide might be helical (ca.8%), but the NMR data show no evidence for a non-linear structure. The observation of reduced amide proton temperature dependence coefficients in certain sections of the molecule can, in view of the absence of any other supporting evidence, only be interpreted in terms of local shielding from solvent for sterical reasons (large hydrophobic side-chains). The conformation of the type III C-telopeptide is mostly extended except for a beta-turn ranging from Gly8 to Glu11, which is stabilized by a hydrogen-bond between NH of Glu11 and the carbonyl group of Gly8. The low temperature coefficient of NH(Glu11) and, in particular, the observation of a medium range NOE between H alpha (A9) and NH(E11) corroborate the existence of a beta-turn in this region. Although spectral overlap prevents a precise conclusion with regard to the type of beta-turn present, there is some evidence that it might be type II.

Amino Acid Sequence↗
PubMed2001

Bacterial expression and conformational analysis of a chemosensory protein from Schistocerca gregaria.

Chemosensory proteins (CSPs) are a class of small, soluble proteins present at high concentrations in chemosensory organs of different insect species. Several pieces of evidence suggest their involvement in carrying chemical messages from the environment to chemosensory receptors. However, a structural description of the mechanism of delivery has not been reported. In order to provide the first detailed conformational characterization of these molecules, we cloned a specific isoform (CSP-sg4) from Schistocerca gregaria and expressed it in Escherichia coli. The product was obtained with yields of more than 20 mg per L of culture, all in its soluble form. The recombinant protein was identical to the native one with respect to pairing of the disulfide bridges, aggregative state and secondary structure elements. Structural investigations revealed a significantly stable polypeptide with respect to variations in temperature and acidity. CD analysis, preliminary NMR data and secondary structure prediction pointed to a correctly folded structure where helical regions and loops are alternated in a similar fashion as that observed for other classes of odorant- and pheromone-binding proteins presenting no sequence similarity to CSPs.

Amino Acid Sequence↗
PubMed1991

Influence of the replacement of amino acid by its D-enantiomer in the sequence of substance P. 2. Conformational analysis by NMR and energy calculations.

The D-enantiomer of residues 2, 4, 5, 6, 7, 8, 10 and 11 was introduced in the sequence of Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH1. The achiral glycine was replaced by a D-Ala residue. The conformations of the D-substituted analogues were analysed by NMR and molecular energy calculations. Introduction of a D-amino acid in the address sequence of SP (1 to 5) distorted the helical structure of [D-Pro2]SP and [D-Pro4]SP. A D-glutamine in position 5 hampered the formation of an helix, the core of [D-Gln5]SP was stabilized by the presence of two beta-turns. The exact fitting of both Phe7 and Phe8 in the binding pocket can be achieved by either an alpha- or a 3(10) helix or two beta-turns types I and II'. Replacement of an amino acid in the message sequence, 6 to 11, drastically decreased the potencies of the corresponding analogues, different conformational modifications were observed. [D-Gln6]SP presented two beta-turns, however, the types of beta-turns should orientate the side-chains in such a way that [D-Gln6]SP did not fit in the binding site. The conformations of [D-Phe7]SP and [D-Phe8]SP were completely changed, a more or less extended structure being observed. Modifications in the Gly-Leu-Met-NH2 sequence did not affect the helical structure of the core of [D-Ala9]SP, [D-Leu10]SP and [D-Met11]SP, but decreased the percentage of extended structure of the C-terminal tripeptide.

Amino Acid Sequence↗
PubMed1991

N.m.r. and conformational analysis of the capsular polysaccharide from Streptococcus pneumoniae type 4.

The 1H- and 13C-n.m.r. data on the capsular polysaccharide (1) produced by Streptococcus pneumoniae type 4, the depyruvated polysaccharide (2), and a tetrasaccharide (3a) derived by Smith degradation of 2 were used as constraints on a computer-generated model of the conformation of 1 and to assess the effects of the pyruvic acetal substituent on the conformation. The dynamics of the polysaccharide systems and the influence of the pyruvic acetal were investigated using 13C-n.m.r. relaxation measurements.

Amides↗
PubMed2000

Alpha-ketoamides and alpha-ketocarbonyls: conformational analysis and development of all-atom OPLS force field.

The molecular structures and barriers for the internal rotation around the OC-CO single bond in four alpha-ketoamides and eight alpha-ketocarbonyls have been determined from the MP3/aug-cc-pVDZ and MP2/aug-cc-pVDZ calculations. Alpha-ketocarbonyls with non-bulky substituents adopt planar conformations with two carbonyl oxygens in s-trans arrangement. The s-cis conformation is significantly less stable due to the electrostatic repulsion between the two carbonyl groups. Primary and secondary alpha-ketoamides are planar when the substituent at the carbonyl carbon is hydrogen or methyl group but tertiary alpha-ketoamides adopt a conformation where the OC-CO unit is significantly bent. Based on current ab initio structural data, a set of OPLS-AA force field parameters has been derived. These parameters can be used for the modeling of a variety of alpha-ketoamide or alpha-ketocarbonyl containing drugs such as novel protease inhibitors or neuroregenerative polyketides.

Amides↗
PubMed1984

Proton NMR study and conformational analysis of d(CGT), d(TCG) and d(CGTCG) in aqueous solution. The effect of a dangling thymidine and of a thymidine mismatch on DNA mini-duplexes.

Proton NMR studies of d(CGT), d(TCG) and d(CGTCG) were carried out at 300 and 500 MHz. The temperature and concentration dependence of the chemical shifts of various resonances indicates duplex formation only in the cases of d(TCG) and d(CGTCG). It is concluded that d(TCG) forms a mini-duplex stabilized by a 5'-dangling thymine base. Thermodynamic parameters of the duplex-to-coil equilibrium of the d(TCG) duplex are: delta H0 = -22.3 kcal/mol and delta S0 = -70 cal/mol. K, which correspond to approximately 40% duplex formation at 0 degrees C in a 2 mM nucleotide solution. Comparison of these data with thermodynamic parameters given earlier [Borer, P.N., Dengler, B., Tinoco, I. and Uhlenbeck, O.C. (1974) J. Mol. Biol. 86, 843-853] leads to the conclusion that the dangling base stabilization observed here is approximately equivalent to the stabilization caused by one or two additional A . T base pairs. The chemical shift behaviour of various resonances in d(CGTCG) indicates duplex formation without looping out of the thymine bases. The T X T mismatch does not seem to disturb the helical structure to a large extent. Analysis of the vicinal proton-proton coupling constants of the three compounds yielded geometrical data for the sugar rings. The data are interpreted in terms of N and S pseudorotational ranges. It is shown that a distinct conformation-transmission effect is exerted by the guanosine residues in a 5'----3' direction.

Magnetic Resonance Spectroscopy↗