RESUMO
The human 5-LOX enzyme and its interaction with competitive inhibitors were investigated by means of a combined ligand-based and target-based approach. First, a pharmacophore model was generated for 16 non redox 5-LOX inhibitors with Catalyst (HipHop module). It includes two hydrophobic groups, an aromatic ring, and two hydrogen bond acceptors. The 3D structure of human 5-LOX was then modeled based on the crystal structure of rabbit 15-LOX, and the binding modes of representative ligands were studied by molecular docking. Confrontation of the docking results with the pharmacophore model allowed the weighting of the pharmacophoric features and the integration of structural information. This led to the proposal of an interaction model inside the 5-LOX active site, consisting of four major and two secondary interaction points: on one hand, two hydrophobic groups, an aromatic ring, and a hydrogen bond acceptor, and, on the other hand, an acidic moiety and an additional hydrogen bond acceptor.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Inibidores de Lipoxigenase , Sequência de Aminoácidos , Animais , Araquidonato 15-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/química , Simulação por Computador , Sequência Consenso , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Conformação Proteica , Estrutura Terciária de Proteína , Coelhos , Relação Estrutura-AtividadeRESUMO
A four-point pharmacophore of COX-2 selective inhibitors was derived from a training set of 16 compounds, using the Catalyst program. It consists of a H bond acceptor, two hydrophobic groups and an aromatic ring, in accordance with SAR data of the compounds and with topology of the COX-2 active site. This hypothesis, combined with exclusion volume spheres representing important residues of the COX-2 binding site, was used to virtually screen the Maybridge database. Eight compounds were selected for an in vitro enzymatic assay. Five of them show COX-2 inhibition close to that of nimesulide and rofecoxib, two reference COX-2 selective inhibitors. As a result, structure-based pharmacophore generation was able to identify original lead compounds, inhibiting the COX-2 isoform.
Assuntos
Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/química , Sistemas de Gerenciamento de Base de Dados , Sítios de Ligação , Humanos , Modelos Moleculares , Estrutura MolecularRESUMO
In this paper, the binding mode of original pyridinic compounds structurally related to nimesulide, a preferential cyclooxygenase (COX)-2 inhibitor, is analyzed by docking simulations in order to understand structure-activity relationships of this family. Structural modifications are proposed to reverse the selectivity of the more active inhibitor of the series characterized by a preferential activity on COX-1. On the basis of these modifications, a new compound with a bromo substituent was designed and showed a COX-2 selective inhibition.
Assuntos
Ciclo-Oxigenase 2/efeitos dos fármacos , Piridinas/química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Cristalografia por Raios X , Ciclo-Oxigenase 1/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Compound 7, N-(3-phenoxy-4-pyridinyl)trifluoromethanesulfonamide, showed in vitro (whole blood assay) a strong inhibitory activity on the two cyclooxygenase (COX) enzymes (IC(50)(COX-1) = 2.2 microM and IC(50)(COX-2) = 0.4 microM), being more active but less COX-2-selective than nimesulide. Physicochemical studies and structural analyses indicated that the anionic sulfonamidate species seemed to be the active form of methanesulfonamides, which optimally interacted with the COX enzymes' active sites.
Assuntos
Aminopiridinas/química , Inibidores de Ciclo-Oxigenase/química , Isoenzimas/antagonistas & inibidores , Sulfonamidas/química , Aminopiridinas/farmacologia , Animais , Ânions , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Humanos , Técnicas In Vitro , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases , Ratos , Ratos Wistar , Espectrofotometria Infravermelho , Sulfonamidas/farmacologiaRESUMO
A new series of nonpeptide AT(1) receptor antagonists were recently developed, based on the structure of irbesartan (Le Bourdonnec et al. J. Med. Chem. 2000, 43, 2685-2697). The lead compound 1 displayed high selectivity for the AT(1) receptor subtype but lower binding affinity than irbesartan. As expected from molecular modeling studies, extension of the pyrazolidine-3,5-dione scaffold to the six-membered heterocycle tetrahydropyridazine-3,6-dione led to an enhancement of the binding affinity toward the AT(1) receptor.
Assuntos
Angiotensina II/metabolismo , Anti-Hipertensivos/química , Compostos de Bifenilo/química , Pirazóis/química , Piridazinas/química , Receptores de Angiotensina/química , Tetrazóis/química , Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Cristalografia por Raios X , Humanos , Irbesartana , Modelos Moleculares , Pirazóis/farmacologia , Piridazinas/farmacologia , Receptor Tipo 1 de Angiotensina , Receptores de Angiotensina/metabolismo , Relação Estrutura-Atividade , Tetrazóis/farmacologia , Células Tumorais CultivadasRESUMO
The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and in vitro pharmacological properties of diarylpyrazole derivatives that have in their structure key pharmacophoric elements to obtain optimal interaction with subsites of active pockets in both enzyme systems. Using a molecular modeling approach, a set of SAR data is proposed, highlighting the importance of the sulfonyl group of one of the aryl moieties in terms of proliferation inhibition and/or apoptosis induction.
Assuntos
Antineoplásicos/síntese química , Apoptose , Isoenzimas/antagonistas & inibidores , Inibidores de Lipoxigenase , Pirazóis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Araquidonato 5-Lipoxigenase/química , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetinae , Ciclo-Oxigenase 2 , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoenzimas/química , Masculino , Proteínas de Membrana , Modelos Moleculares , Prostaglandina-Endoperóxido Sintases/química , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
The use of metal-organic complexes is a potentially fruitful approach for the development of novel enzyme inhibitors. They hold the attractive promise of forming stronger attachments with the target by combining the co-ordination ability of metals with the unique stereoelectronic properties of the ligand. We demonstrated that this approach can be successfully used to inhibit the protease of the human immunodeficiency virus (type 1). Several ligands bearing substituents designed to interact with the catalytic site of the enzyme when complexed to Cu(2+) were synthesised. The inhibition pattern of the resulting copper(II) complexes was analysed. We showed that the copper(II) complex of N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide (C1) interacts with the active site of the enzyme leading to competitive inhibition. On the other hand, N2-pyridine-amide ligands and oxazinane carboxamide ligand were found to be poor chelators of the cupric ion under the enzymatic assay conditions. In these cases, the observed inhibition was attributed to released cupric ions which react with cysteine residues on the surface of the protease. While unchelated metal cations are not likely to be useful agents, metal chelates such as C1 should be considered as promising lead compounds for the development of targeted drugs.
Assuntos
Benzamidas/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Compostos Organometálicos/farmacologia , Piridinas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Desenho de Fármacos , Espectroscopia de Ressonância de Spin Eletrônica , Protease de HIV/química , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Humanos , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Piridinas/síntese química , Piridinas/químicaRESUMO
A 3D pharmacophore model was developed for original sulphonyl-urea (-cyanoguanidine) compounds and known molecules which behave both as thromboxane receptor antagonists and as thromboxane synthase inhibitors. Five recognition sites appear to be essential for this dual activity: two hydrogen bond acceptors, an anionic site, a hydrophobic group and an aromatic ring. Such a model could be used to design new leads possessing the same pharmacological profile and to improve the activity of our compounds.
Assuntos
Receptores de Tromboxanos/antagonistas & inibidores , Compostos de Sulfonilureia/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Sítios de Ligação , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Guanidinas/química , Guanidinas/farmacologia , Humanos , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Compostos de Sulfonilureia/químicaRESUMO
Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC(50). Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Viral/efeitos dos fármacos , Simulação por Computador , Cristalografia por Raios X , HIV/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Inibidores da Transcriptase Reversa/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The influence of chemical modification of scanning tunnelling microscopy tips on image contrast is studied. This technique is applied to the identification of an ester functional group, hardly visible otherwise. Self-assembled overlayers of wax esters [CH3-(CH2)14-CO-O-(CH2)15-CH3], adsorbed at the interface between highly oriented pyrolitic graphite and a solution of phenyloctane, are imaged. The gold tips used are chemically modified by 4-mercaptobenzoic acid and 4-mercaptotoluene. The stability of the ordered overlayers formed facilitates the reproducible set of images with submolecular resolution. This allows the identification of the layer regular structure and of other features within molecules, which can be unambiguously related to the fingerprints of the COO bond. Moreover, we are interested in finding evidence of molecular motions observed at domain boundaries.
RESUMO
The structures of three compounds, namely 7-methoxy-2-[3-(trifluoromethyl)phenyl]-9H-indeno[1,2-c]pyridazin-9-one, C19H11F3N2O2, (Id), 6-methoxy-2-[3-(trifluoromethyl)phenyl]-9H-indeno[1,2-c]pyridazin-9-one, C19H11F3N2O2, (IId), and 2-methyl-6-(4,4,4-trifluorobutoxy)-9H-indeno[1,2-c]pyridazin-9-one, C16H13F3N2O2, (IIf), which are potent reversible type-B monoamine oxidase (MAO-B) inhibitors, are presented and discussed. Compounds (Id) and (IId) crystallize in a nearly planar conformation. The crystal structures are stabilized by weak C-H...O hydrogen bonds. The packing is dominated by pi-pi stacking interactions between the heterocyclic central moieties of centrosymmetrically related molecules. In compound (IIf), the trifluoroethyl termination is almost perpendicular to the plane of the ring.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Indenos/química , Inibidores da Monoaminoxidase/química , Piridazinas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura MolecularRESUMO
Three related compounds containing a pyrazole moiety with vicinal phenyl rings featuring a methylsulfonyl substituent are described, namely 3-methyl-1-[4-(methylsulfonyl)phenyl]-5-phenyl-1H-pyrazole, C17H16N2O2S, ethyl 1-[4-(methylsulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-carboxylate, C19H18N2O4S, and 1-[4-(methylsulfonyl)phenyl]-3-[3-(morpholino)phenoxymethyl]-5-phenyl-1H-pyrazole, C27H27N3O4S. The design of these compounds was based on celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in order to study the influence of various substituents on COX-2 and 5-lipoxygenase (5-LOX) inhibition.
RESUMO
A pharmacophore associated to the inhibiton of alpha-chymotrypsin has been built based on the structural and electronic characterization of a series of coumarin derivatives.
Assuntos
Anticoagulantes/farmacologia , Quimotripsina/antagonistas & inibidores , Cumarínicos/farmacologia , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Modelos Moleculares , Modelos EstruturaisRESUMO
The title compound (BM531), C(17)H(26)N(4)O(5)S, has been designed for use as both a thromboxane synthase inhibitor (TXSI) and a thromboxane receptor antagonist (TXRA). We report here the X-ray crystal structure determination of the compound.
Assuntos
Receptores de Tromboxanos/antagonistas & inibidores , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Conformação Molecular , Estrutura MolecularRESUMO
The title compound, C(12)H(12)N(2)O(3)S, is a strict pyridine analogue of nimesulide, a selective inhibitor of cyclooxygenase-2. The structure is characterized by a pyridinium ring with a deprotonated sulfonamide group. An intermolecular charge-assisted hydrogen bond between these two groups is observed within the crystal packing, linking the molecules into an infinite chain running along the b-axis direction.
Assuntos
Aminopiridinas/química , Inibidores de Ciclo-Oxigenase/química , Isoenzimas/antagonistas & inibidores , Sulfonamidas/química , Cristalografia por Raios X , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Ligação de Hidrogênio , Modelos Moleculares , Prostaglandina-Endoperóxido SintasesRESUMO
The stereoelectronic properties of several potent reversible monoamine oxidase B (MAO-B) inhibitors were studied with a view to develop a pharmacophore model for reversible MAO-B inhibition. This study suggested that important specific H-bond and hydrophobic interactions are required for potent and selective MAO-B inhibition. These requirements were applied in the design and synthesis of a novel reversible and selective MAO-B inhibitor, 3-methyl-8-(4,4,4-trifluoro-butoxy)indeno[1,2-c]pyridazin-5-one, that is ca. 7000 times more selective as an inhibitor for MAO-B than for MAO-A, with K(i(MAO-B)) in the low nanomolar range.