RESUMO
The crystal structures of three angiotensin-II receptor antagonists involving different spacer groups (CO, CONH and NHCO) between the aryl rings are presented, namely 2-[4-[(3-butyl-1,4-dioxo-2,3-diazaspiro[4.4]non-2-yl)methyl]benzoyl]benzoic acid, C(26)H(28)N(2)O(5), (I), 2-[4-[(3-butyl-1,4-dioxo-2,3-diazaspiro[4.4]non-2-yl)methyl]benzamido]benzoic acid, C(26)H(29)N(3)O(5), (II), and 2-[4-[(3-butyl-1,4-dioxo-2,3-diazaspiro[4.4]non-2-yl)methyl]anilinocarbonyl]benzoic acid monohydrate, C(26)H(29)N(3)O(5) x H(2)O, (III). The aryl rings of (II) are almost coplanar, in contrast with compounds (I) and (III). The conformation of (II) is induced by an intramolecular N-H.O hydrogen bond between the amide and carboxylic acid groups.
Assuntos
Angiotensina II , Antagonistas de Receptores de Angiotensina , Pirazóis/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Conformação MolecularRESUMO
Previous investigations of the potential of metal-organic compounds as inhibitors of human immunodeficiency virus type I protease (HIV-1 PR) showed that the copper(II) complex diaqua [bis(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate and the complex bis[N2-(2,3,6-trimethoxybenzyl)-4-2-pyridinecarboxamide] copper(II) behaved as inhibitors of HIV-1 PR. In a search for similar readily accessible ligands, we synthesised and studied the structural properties of N2-(2-pyridylmethyl)-2-pyridinecarboxamide (L) copper(II) complexes. Three different crystal structures were obtained. Two were found to contain ligand L simultaneously in a tridentate and bidentate conformation [Cu(L(tri)L(bi))]. The other contained two symmetry-related ligands, coordinated through the pyridine nitrogen and the amide oxygen atoms [Cu(L(bi))(2)]. A search of the Cambridge Structural Database indicated that L(tri) resulting from nitrogen bound amide hydrogen metal substitution is favoured over chelation through the amide oxygen atom. In our case, we calculated that the conformation of L(tri) is 11 kcal/mol more favourable than that of L(bi). ESI-MS experiments showed that the Cu(L(bi))(2) structure could not be observed in solution, while Cu(L(tri)L(bi))-related complexes were indeed present. The lack of protease inhibition of the pyridine carboxamide copper(II) complexes was explained by the fact that the Cu(L(bi)L(tri)) complex could not fit into the HIV-1 active site.
Assuntos
Cobre/química , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Piridinas/química , Piridinas/síntese química , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Técnicas In Vitro , Modelos Moleculares , Compostos Organometálicos/farmacologia , Piridinas/farmacologia , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
BM567, a sulfonylurea compound whose crystal structure is here discussed and terbogrel, are both thromboxane receptor antagonists and thromboxane synthase inhibitors. In this paper, their crystallographic and electronic structures are compared and lead to new synthesis prospects among the sulfonylurea series.
Assuntos
Piridinas/química , Piridinas/farmacologia , Receptores de Tromboxanos/antagonistas & inibidores , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Cristalografia , Ligação de Hidrogênio , Conformação Molecular , Estrutura Molecular , Espectrofotometria Atômica/métodos , Eletricidade EstáticaRESUMO
The synthesis and the structure of N-isopropyl-N'-[2-(3'-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 microM) with an IC50 value of 0.45 and 0.15 microM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 microM) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.
Assuntos
Receptores de Tromboxanos/antagonistas & inibidores , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Ácido Araquidônico/farmacologia , Cobaias , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Tromboxano-A Sintase/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
The structures, electronic (charges, molecular electrostatic potential, molecular orbitals) and lipophilic properties of three isostere analogues of torasemide were determined and the influence of the replacement of the sulfonyl urea group on the conformation and electronic properties of the molecules is discussed. Lipophilicity of the compounds seems to be the most discriminating property along the series and affects their pharmacological activities.
Assuntos
Diuréticos/química , Sulfonamidas/química , Animais , Cristalografia , Diuréticos/farmacologia , Isomerismo , Conformação Molecular , Relação Quantitativa Estrutura-Atividade , Ratos , Sulfonamidas/farmacologia , TorasemidaRESUMO
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor activated by hypoxia. When activated, HIF-1 mediates the differential expression of genes such as erythropoietin and Vascular Endothelial Growth Factor (VEGF) during hypoxia. It is composed of two different subunits, HIF-1alpha and ARNT (Aryl Receptor Nuclear Translocator). These two subunits belong to the bHLH (basic Helix-Loop-Helix) PAS (Per, Ahr/ARNT, Sim) family. The bHLH domain of these factors is responsible for dimerization through the two helices and for DNA binding through their basic domain. In this work, we used various methods of molecular modeling in order to develop a 3D structure for the HIF-1 bHLH domain bound to its DNA consensus sequence. Firstly, the 3D structure of the bHLH domain of both subunits based on their amino acid sequence was defined. Secondly, we compared this model with data from known crystal structures of basic leucine zipper-DNA and bHLH-DNA complexes in order to determine a potential canvas for HIF-1. Thirdly, we performed a manual approach of the HIF-1 bHLH domain onto the DNA recognition site using this canvas. Finally, the protein-DNA complex 3D structure was optimized using a Monte Carlo program called MONTY. The model predicted a pattern of interactions between amino acids and DNA bases which reflect for ARNT what is experimentally observed among different X-ray structures of other bHLH transcription factors possessing the H (His), E (Glu), R (Arg) triad, as ARNT does. On the other hand, only the Arg residue is conserved in HIF- 1alpha. We propose from this model that a serine replaces the histidine while an alanine and a lysine also make contacts with DNA. From these results, we postulate that the specificity of HIF-1 toward its DNA sequence could be driven by the HIF-1alpha subunit. The predicted model will be verified by X-Ray currently ongoing.
Assuntos
Proteínas de Ligação a DNA/química , Proteínas Nucleares/química , Alanina/química , Sequência de Aminoácidos , Animais , Cristalografia , Dimerização , Eritropoetina/química , Histidina/química , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Lisina/química , Modelos Moleculares , Dados de Sequência Molecular , Método de Monte Carlo , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Análise de Sequência de DNA , Serina/química , Software , Fatores de Transcrição/químicaRESUMO
Terbogrel, (E)-6-[4-(3-tert-butyl-2-cyanoguanidino)phenyl]-6-(3-pyridyl)hex-5 -enoic acid, C(23)H(27)N(5)O(2), a mixed thromboxane A(2) receptor antagonist and thromboxane A(2) synthase inhibitor, shows a hairpin-like conformation stabilized by an intramolecular hydrogen bond. A structural feature characteristic of the thromboxane A(2) synthase inhibitor mode is observed: a distance of 8.4257 (19) A between the pyridine N atom and the carboxyl group.
Assuntos
Inibidores Enzimáticos/química , Piridinas/química , Receptores de Tromboxanos/antagonistas & inibidores , Tromboxano-A Sintase/antagonistas & inibidores , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Conformação MolecularRESUMO
Among the various chemical classes of monoamine oxidase A inhibitors, phenyloxazolidinone represent one of the major series. The purpose of this paper is to review the experimental (X-ray diffraction, NMR, electronic absorption spectroscopy, lipophilicity studies) and theoretical (quantum chemistry, molecular mechanics, molecular dynamics) studies which have led to the description of the mode of interaction between phenyloxazolidinone inhibitors and the MAO-A enzyme.
Assuntos
Modelos Moleculares , Inibidores da Monoaminoxidase/química , Monoaminoxidase/química , Animais , Cristalização , Humanos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacocinéticaRESUMO
The major goal of the present work is to further approach the structure of human monoamine oxidase A (MAO-A). A first partial three-dimensional model of human MAO-A has already been established using secondary structure predictions and fold recognition methods [Wouters and Baudoux, 1998]. In this modeled structure, a segment of the sequence (residues 369-393) located near the covalent linkage to the essential flavin cofactor, and potentially involved in the structure of the active site of the protein, could not be modeled. We here propose a possible fold for that segment, based on threading techniques. The identification of regions of the protein potentially involved in its dimerization was also undertaken by studying hydrophobic areas present at the surface of the structure.
Assuntos
Modelos Moleculares , Monoaminoxidase/química , Humanos , Conformação ProteicaRESUMO
This work reports on the structure of trielaidin [EEE, 1,2,3-tri(trans-9-octadecenoyl)glycerol], a trans unsaturated triglyceride present in many refined fatty materials (margarines, chocolate products etc.). Firstly, the polymorphism, i.e. the existence of different crystalline forms at various temperature ranges, was defined. Secondly, the crystal growth was examined. By developing a particular growing system, monocrystals of the most stable polymorphic form, i.e. the beta-form, were obtained. To reduce thermal vibrations the X-ray data were collected at low temperature (173 K) and the structure was solved using direct methods. The structure was then analyzed in terms of conformation and crystal packing and compared with those of the other known triglycerides.
RESUMO
The crystal structure of seratrodast (AA-2414), a potent thromboxane A2 (TXA2) receptor antagonist, served as starting point to docking studies with the modeled human TXA2 receptor. This structural approach provides rational basis for the design of new antagonists within the aryl sulfonamide family.
Assuntos
Benzoquinonas/química , Ácidos Heptanoicos/química , Antagonistas de Prostaglandina/química , Receptores de Tromboxanos/química , Animais , Benzoquinonas/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Cobaias , Ácidos Heptanoicos/farmacologia , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Antagonistas de Prostaglandina/farmacologia , Receptores de Tromboxanos/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.
Assuntos
Inibidores da Monoaminoxidase/farmacologia , Oxazóis/farmacologia , Animais , Cristalografia por Raios X , Ligação de Hidrogênio , Masculino , Conformação Molecular , Inibidores da Monoaminoxidase/química , Oxazóis/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
X-ray diffraction and ab initio MO theoretical calculations were used in order to investigate the structural and electronic properties of sarmazenil, a weak inverse agonist at the omega modulatory sites (benzodiazepine receptors). This compound was compared to bretazenil, a partial agonist, and to the antagonist flumazenil on the basis of structural and electronic data. The conformational and theoretical properties (interatomic pi overlap populations, molecular electrostatic potential (MEP), the topology of frontier orbitals, and proton affinity) of these three imidazobenzodiazepinones were determined in order to analyse the stereoelectronic properties in relation with their distinct intrinsic efficacies at the omega modulatory sites.
Assuntos
Benzodiazepinas/química , Benzodiazepinonas/química , Flumazenil/química , Agonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-A , Imidazóis/química , Benzodiazepinas/metabolismo , Benzodiazepinonas/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Flumazenil/metabolismo , Imidazóis/metabolismo , Modelos Moleculares , Conformação Molecular , Estrutura MolecularRESUMO
SR 142948 is an original and extremely potent neurotensin receptor antagonist developed in a promising approach to novel antipsychotic drugs. The X-ray structure was elucidated and compared to SR 48692 and levocabastine, providing new informations about the possible recognition process of NT receptor subtypes.
Assuntos
Pirazóis/química , Quinolinas/química , Receptores de Neurotensina/antagonistas & inibidores , Animais , Cristalografia por Raios X , Camundongos , Modelos Moleculares , Piperidinas/química , Conformação Proteica , Pirazóis/farmacologia , Quinolinas/farmacologia , RatosRESUMO
The capacity factor of eleven derivatives belonging to a prototype series of 3-phenyloxazolidin-2-one, reversible MAO inhibitors, was measured and compared to the calculated log Pcalc using the CLIP package. We demonstrate that this Molecular Lipophilicity Potential (MLP) approach is a valuable tool to estimate log Pcalc of such compounds.
Assuntos
Lipídeos/química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Oxazóis/síntese química , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Modelos Químicos , Oxazóis/farmacologia , Análise de Regressão , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
The crystal structures of 5-(5-furan-2-yl)-2'-deoxyuridine (II), 5-(5-bromofuran-2-yl)-2'-deoxyuridine (IV) and 5-(3-bromothien-2-yl)-2'-deoxyuridine (V) have been studied in order to explain the different affinity of the compounds for the herpes simplex virus type 1 (HSV-1) thymidine kinase. These compounds present a variable affinity according to the position of the heteroatom substituting the five-membered ring. An unfavourable substitution in the five-membered ring for interaction with the HSV-1 thymidine kinase has been identified.
Assuntos
Antivirais/química , Antivirais/metabolismo , Bromo , Desoxiuridina/química , Desoxiuridina/metabolismo , Herpesvirus Humano 1/enzimologia , Timidina Quinase/metabolismo , Desoxiuridina/análogos & derivados , Humanos , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/metabolismo , Difração de Raios XRESUMO
Crystallographic database studies and molecular dynamics simulations in different media have enabled us to sample the conformational space of a GABAB antagonist. As a result, we have defined a pharmacophoric pattern for GABAB antagonists. This study has led us to compare the conformational preferences deduced from database studies and molecular dynamics simulations. The influence of the medium on the conformations has also been investigated.
Assuntos
Antagonistas GABAérgicos/química , Antagonistas de Receptores de GABA-B , Modelos Moleculares , Baclofeno/análogos & derivados , Baclofeno/química , Simulação por Computador , Cristalografia , Bases de Dados Factuais , Agonistas GABAérgicos/química , Conformação Molecular , TermodinâmicaRESUMO
Substituting a furan, a thiophene, a benzo[b]furan, a benzo[b]thiophene, or a quinoline ring for the p-chlorophenyl moiety of baclofen has led to GABAB ligands with different affinities depending on the nature of the heteroaromatic ring, and on the nature and position of its substituent. As steric effects cannot account for all the affinity variations, we have studied the lipophilic and electronic properties of baclofen and selected 3-heteroaromatic analogues, gaining insight into the structural features necessary for GABAB affinity. Centrifugal partition chromatography (CPC) has been used to measure octan-1-ol water distribution coefficients, while ab initio molecular orbital (MO) calculations were performed to study electronic properties.
Assuntos
Baclofeno/análogos & derivados , Baclofeno/química , Agonistas GABAérgicos/química , Baclofeno/farmacologia , Conformação Molecular , Receptores de GABA-B/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
The secondary structure of human monoamine oxidase A and bovine monoamine oxidase B has been investigated by Fourier Transform Attenuated Total Reflection Spectroscopy (FTIR ATR). The experimental results are compared for both isoenzymes and the data are incorporated in a statistical attribution of secondary structure of the enzyme describing the distinct folding and molecular specificity of the two types of monoamine oxidase.