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At least 19 recordsLinked to original sources
PubMed1991

Crystal structure and molecular structure of mefloquine methylsulfonate monohydrate: implications for a malaria receptor.

The crystal structure of (+/-)-mefloquine methylsulfonate monohydrate was determined by X-ray diffraction and was compared with the crystal structures of mefloquine hydrochloride and mefloquine free base. The conformation of mefloquine was essentially the same in all three crystalline environments and was not dependent on whether mefloquine was a salt or a free base. In mefloquine methylsulfonate monohydrate, the angle between the average plane of the quinoline ring and the average plane of the piperidine ring was 76.9 degrees. The intramolecular aliphatic N-13...O-1 distance was 2.730 +/- 0.008 A (1 A = 0.1 nm), which is close to the aliphatic N...O distance found in the antimalarial cinchona alkaloids. The hydroxyl group formed a hydrogen bond with the water molecule, and the amine group formed hydrogen bonds with two different methylsulfonate ions. The crystallographic parameters for (+/-)-mefloquine methylsulfonate monohydrate were as follows: C17H17F6N2O(+).CH3SO3(-).H2O; Mr = 492.4; symmetry of unit cell, monoclinic; space group, P2(1)/a; parameters of unit cell, a was 8.678 +/- 0.001 A, b was 28.330 +/- 0.003 A, c was 8.804 +/- 0.001 A, beta was 97.50 +/- 0.01 degrees; the volume of the unit cell was 2145.9 A3; the number of molecules per unit cell was 4; the calculated density was 1.52 g cm(-3); the source of radiation was Cu K alpha (lambda = 1.54178 A); mu (absorption coefficient) was 20.46 cm(-1); F(000) (sum of atomic scattering factors at zero scattering angle) was 1,016; room temperature was used; and the final R (residual index) was 6.58% for 1,740 reflections with magnitude of Fo greater than 3 sigma (F). Since the mechanism of antimalarial action and the mechanism of mefloquine resistance may involve hydrogen bond formation between mefloquine and a cellular effector or transport proteins, the common conformation of mefloquine found in each crystalline environment may define the orientation in which mefloquine forms these potentially critical hydrogen bonds with cellular constituents.

Crystallization↗
PubMed1988

Thyroid hormone structure-activity relationships: molecular structure of 3,5,3'-triiodothyropropionic acid.

The crystal and molecular structures of 3,5,3'-triiodothyropropionic acid (T3P), determined as an N-diethanolamine salt, were carried out and the results are compared with those of other thyroid hormone structures. These data show that T3P has an unusual conformation with the diphenyl ether bridge outside the range normally observed for other thyroactive acid structures and has the largest deviations from the ideal skewed conformation predicted for 3,5-diiodothyroactive compounds. These conformational properties are not observed in the structures of thyroformic or acetic acid analogues. Biochemical data indicate that thyropropionic acid analogue activity differs from that other acid analogues which could imply that their metabolism and activity can be controlled differently from that of other hormone metabolites.

Crystallography↗
PubMed1992

Molecular structure and dynamics of the four 10-hydroxynortriptyline isomers.

The three-dimensional structures, molecular conformations, and electrostatic potentials of the R-E-, S-E-, R-Z-, and S-Z-isomers of 10-hydroxynortriptyline were examined by computer graphics, molecular mechanical energy calculations, and molecular dynamics simulations in vacuo and in aqueous solution. Molecular models of the isomers, based on the structure of nortriptyline, were refined by energy minimization and used as starting points in the simulations. R-E- and S-Z-10-hydroxynortriptyline formed intramolecular hydrogen bonds between the side-chain nitrogen atom and the hydroxyl group during the simulations in vacuo, and had the side chain folded over the ring system in the minimum energy conformations. Intramolecular hydrogen bonding was not observed for R-Z- and S-E-10-hydroxynortriptyline, which had extended side chains in the minimum energy conformations and stronger negative molecular electrostatic potentials around the hydroxyl group than the R-E- and S-Z-isomers.

Models, Molecular↗
PubMed1992

Alpha-beta-dehydro-amino acid residues in the design of peptide structures. Molecular and crystal structures of two folded dehydro peptides.

The molecular and crystal structures of two N alpha-protected tripeptide amides, containing in the central position the alpha-beta-dehydro-amino acid residue delta Phe (Z-configurational isomer), were determined by X-ray diffraction. While Z-Gly-delta Phez-L-Pro-NH2 is characterized in the crystal state by the presence of a type I beta-bend conformation (at the delta Phez-L-Pro sequence), Z-D-Ala-delta Phez-Gly-NH2 is folded into two consecutive beta-bends (type II' followed by type I), at the D-Ala-delta Phez and delta Phez-Gly sequences, respectively. In both cases the achiral delta Phez residue adopts a set of phi, psi angles typical of the right-handed helical conformation. The delta Phe residue may be exploited to design aromatic peptides with preferred secondary structures.

Amino Acid Sequence↗
PubMedDate not supplied

[Optical properties and molecular structure of nucleic acids and their components. X. Infrared spectra and molecular structure of denatured DNA with different water content and degree of protonation].

IR-spectra (4000-900 cm-minus-1) of heat denatured DNA (d-DNA) of calf thymus have been obtained in the range of relative humidity of 0-93% and of the guota of protoned bases alpha of 0-0,5. fron these spectra the diagram of d-DNA states is plotted as the relationships of intensities and the location of some bands with and relative humidity. At alpha approximately 0,2 a compact structure S2-1 with firm hydrogen bonds between protoned and unprotoned bases which is similar to those observed earlier while protoning homopolynucleotides poly-A and poly-C. At G1'-large values of alpha S2-1-conformation destroyed and a loose structure (alpha approximately 0,35) appears. the latter is characterized by a minimum H-binding of the base and increased hydration. Further increase of alpha brings about the formation of sufficiently compact G2-1-STRUCTURE WHICH IS CHARACTERIZED BY SOLID H-bonds between PO2-groups and protoned bases. A specific effect of the structures found on the state of absorbed water and the structure of hydrate envelope is revealed.

Animals↗
PubMed1991

Molecular structure, polymorphism, and toxicity of lantadene A, the pentacyclic triterpenoid from the hepatotoxic plant Lantana camara.

Lantadene A (22 beta-angeloyloxy-3-oxo-olean-12-en-28-oic acid), a pentacyclic triterpenoid compound from lantana (Lantana camara) leaves has been obtained in two polymorphic forms I and II. Form I had white, fluffy, and rod-shaped uniform crystals. Form II particles were irregular, shining, and polyhedral. The two forms differed in melting behavior. The powder x-ray diffraction of form I showed sharp peaks whereas from II did not contain distinct peaks. From single-crystal three-dimensional x-ray structure determination, the molecular structure of form I has been established. A/B and B/C rings of the molecule are trans fused while D/E rings are cis fused. The packing of the molecule is stabilized by hydrogen bonding. Form I of lantadene A was non-toxic to guinea pigs on oral administration. Form II induced ictericity and toxicity associated with decrease in feed intake and fecal output, hepatomegaly, increase in plasma bilirubin, and acid phosphatase activity.

Animals↗
PubMed1989

[X-ray structural studies of nucleic acid molecular structure and nucleic acid-protein interaction mechanism].

Since the discovery of the right-handed double helical structure of deoxyribonucleic acid by Watson and Crick in 1953, many pieces of detailed nucleic acid structural information involving ribonucleic acid have been elucidated and this review describes the results of the X-ray structural studies of nucleic acids and their constituents carried out in my laboratory. In the latter half the nucleic acid-protein interaction mechanism was also discussed on the basis of the molecular model of the stacking interaction between base and aromatic amino acid side chains. The structure-function relationship of ribonuclease T1.guanosine monophosphate complex was used as an example.

Binding Sites↗
PubMed1992

Structural studies on H2-antagonists: crystal and molecular structure of N-cyano-N'-methyl-N"-(2-[(2-amino-5-thiazolyl)methylthio]ethyl) guanidine and N-cyano-3-[(2-guanidino-5-thiazolyl)methylthio]propionamidine.

The crystal and molecular structures of N-cyano-N'-methyl-N"-(2-[(2-amino-5-thiazolyl) methylthio] ethyl) guanidine and N-cyano-3-[(2-guanidino-5-thiazolyl)methylthio]propionamidine are reported. Both molecules are in an extended conformation. In all two crystals a system of hydrogen bonds links the molecules in a three-dimensional network. A comparison with the structure of cimetidine and famotidine is also included.

Cimetidine↗
PubMed1991

Molecular structure and dynamics of cis(Z)-and trans(E)-flupenthixol and clopenthixol.

The three-dimensional structures and molecular electrostatic potentials of the cis(Z) and trans(E)-isomers of flupenthixol and clopenthixol were examined by computer graphics and molecular mechanical and quantum mechanical calculations, and their internal molecular motions were studied by molecular dynamics simulations in vacuo and in aqueous solution. The simulations demonstrated that both the side chains and the tricyclic ring systems of clopenthixol and flupenthixol are highly flexible. The angle between the two phenyl ring planes varied between 105 and 171 degrees during the simulations in solution. The electrostatic potentials around the 2-substituent were significantly more negative in the trans(E)-isomers than in the cis(Z)-isomers. The stronger negative potentials may weaken electrostatic receptor interactions and, thereby, cause the trans(E)-isomers to be less active than cis(Z)-isomers. Differences both in three-dimensional structure and in electronic structure may cause the difference in pharmacological activity between cis(Z)- and trans(E)-thioxanthenes.

Clopenthixol↗
PubMed1991

Structure-activity studies of non-steroidal aromatase inhibitors: the crystal and molecular structures of CGS 16949A and CGS 18320B.

The crystal and molecular structures of 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile hydrochloride (CGS 16949A) and bis(p-cyanophenyl)imidazo-1-yl methane hemisuccinate (CGS 18320B) have been determined as part of structure-activity relationship studies of non-steroidal aromatase inhibitors. CGS 18320B crystallizes with two inhibitor molecules in the asymmetric unit that are similar in conformation. The cyanophenyl groups and the imidazole moieties in the CGS 18320B molecules display a propellor-like arrangement. The orientation of the imidazole ring in CGS 16949A, which is constrained by the piperidine ring, differs by about 80 degrees from the orientations in both CGS 18320B molecules. The conformations of both compounds are consistent with the proposed model (Banting et al. (1988) J. Enz. Inhibit., 2, 216) for inhibitor binding by positioning of the cyanophenyl group in the steroid A-ring binding site and interaction of the imidazole nitrogen with the iron of the haem.

Aromatase Inhibitors↗
PubMed1986

Molecular structure and absolute configuration of suberogorgin.

In the present paper it is reported that the molecular structure and absolute configuration of poisonous suberogorgin are determined by using X-ray diffraction method. The crystal of suberogorgin belongs to orthogonal system with space group D4(2)-P2(1)2(1)2(1). The crystallographic parameters are: a = 16.135A, b = 13.189A, c = 12.901A, Z = 8. The initial model of the crystal structure was solved by the direct method. The refinement of the structure parameters was carried out by using the least square method and led to a final R-factor of 0.056. In accordance with the molecular structure of suberogorgin mentioned above, the solvent effect of NMR has been further discussed and the relationship between the molecular structure of suberogorgin and its toxicity has also been preliminarily investigated.

Animals↗
PubMed1987

Defining the active site of cytochrome P-450: the crystal and molecular structure of an inhibitor, SKF-525A.

The crystal and molecular structure of the cytochrome P-450 inhibitor, SKF-525A [2-(diethylamino)ethyl 2,2-diphenylpentenoate; proadifen hydrochloride] is described. Proadifen hydrochloride crystallized from an ethyl acetate and acetic acid mixture in the space group P2(1)/c with one molecule in the asymmetric unit. Cell constants are a = 18.716(4), b = 8.906(1), c = 14.201(3), beta = 109.41(1) degrees. The structure was solved using direct methods and was refined to an R value of 0.047; weighted R of 0.061 using 3757 reflections. From the crystal and molecular structure, it is seen that SKF-525A has two principal modes of complementary interactions with the enzyme available: polar and non-polar. Polar interactions that principally involve the chloride anion, the quaternary nitrogen atom and the carbonyl oxygen atom. In particular, there are two strong hydrogen bonds, one between Cl ... H-N, 3.090(1) A, the other between O2 ... H-C111 (one of the ethyl hydrogen atoms) at 3.411(2) A. The other is through non-polar interactions involving the phenyl and alkyl groups. Comparisons between proadifen hydrochloride and other inhibitors whose atomic coordinates are available reveal common features which correlate with their function. These include groups to provide necessary intermolecular contacts and bulk, such as a phenyl group and a hydrogen bond acceptor, as well as a tetrahedral atom, which allows for substrate flexibility.

Crystallization↗
PubMed1979

On the molecular structure of some prostaglandin receptors.

Hypotheses are presented of the detailed molecular structure of two prostaglandin receptors both concerned in tumor-promotion processes. These structures have been derived by the comparison of the molecular structure of agents active at the site with (i) a simple theoretical protein structure and (ii) the known x-ray structure of phospholipase A2. The first model receptor is stimulatory to the tumor-promotion process and may be located on the control system for ornithine decarboxylase. The binding of PG here is cooperative with the binding of Ca++. Naturally-occurring agonists at this receptor may include members of the cathartic class of drugs such as colocynth, chrysarobin, etc. Naturally-occurring antagonists at this site may include a number of anti-tumor compounds such as datiscoside. The second model receptor (PGE1) is inhibitory to the tumor-promotion process and is located at a specific allosteric site on the x-ray-determined structure of phospholipase A2. This site overlaps for one for lysolecithin (excitatory), for which tumor-promoting phorbol esters such as TPA are agonists and some anti-tumor drugs such as maytansine may be antagonists.

Antineoplastic Agents↗
PubMed1990

A comparison of the molecular structure of integrated hepatitis B virus genomes in hepatocellular carcinoma cells and hepatocytes derived from the same patient.

To elucidate critical genetic elements in the development of hepatocellular carcinoma associated with hepatitis B virus DNA integration, a single integrant in hepatocellular carcinoma cells and one species of multiple integrants in hepatocytes, both obtained from the same patient, were compared structurally using molecular cloning techniques. Both hepatitis B virus integrants showed similar inverted repeat sequences consisting of two defective virus genomes. The recombination of viral DNAs seemed to be mediated by short regions of base homology near the direct repeat 1 and at other regions of the virus genomes in both integrants. The virus component in the junction with host DNAs was the cohesive end region in each identical end of the viral integrant in hepatocellular carcinoma cells and in one end of the viral integrant in hepatocytes. The structure of the integrant in hepatocellular carcinoma cells was characterized by an inverted, duplicated conformation composed not only of integrated virus genomes but also of flanking cellular sequences. It was shown to be the so-called "alpha dimer" of satellite DNA. In contrast, the flanking, nonreiterated cellular DNA in the hepatocyte-derived clone did not show discernible rearrangement. These findings suggest that a common mechanism underlies the integration of hepatitis B virus DNA so that a similar organization of inverted repeat genomes is found in hepatocellular carcinoma cells and in hepatocytes. The unstable nature of cellular DNA where DNA integration occurs may be important in generating chromosome alterations found in hepatocellular carcinoma.

Adult↗
PubMed1992

Molecular structural basis of ligand selectivity for 5-HT2 versus 5-HT1C cortical receptors.

A molecular structural criterion of ligand selectivity for the 5-HT2 versus 5-HT1C receptor was hypothesized on the basis of radioligand binding data. Despite the large number of compounds which have been tested at both receptors, analysis of published data led to the identification of only five agents which are greater than 10-fold selective for the 5-HT2 versus the 5-HT1C receptor. Comparison of the two-dimensional structures revealed that, although these five compounds represent three distinct structural classes, they share a common structural feature located in the region hypothesized to be involved in receptor binding: a carbonyl or carboxyl oxygen interposed spatially between an aromatic ring and nitrogen atom. This structural feature was used to predict the relative selectivity of compounds that had not previously been analyzed at both the 5-HT2 and 5-HT1C receptors. All six drugs tested which contain the identified reactive carbonyl or carboxyl group were found to be selective for the 5-HT2 versus the 5-HT1C receptor with selectivity ratios ranging from 26 to 380. By contrast, three agents which are structurally similar but do not contain the reactive carbonyl or carboxyl group displayed equally high affinity for both receptor binding sites. Since the physiological roles of the 5-HT2 and 5-HT1C receptor are markedly different, it would be of potential clinical and scientific value to utilize this molecular structural feature to further identify chemical compounds which would selectively interact with only one of the two receptors.

Animals↗