RESUMO
The protection effect of verbascoside (Ver) against Fenton reaction on plasmid pBR322 DNA was studied using agarose gel electrophoresis and UV-visible spectroscopy. The pBR322 plasmid DNA is damaged by hydroxyl radical (OH*) generated from the Fenton reaction with H2O2 and Fe(II) or Fe(III). This DNA damage is characterized by the diminution of supercoiled DNA forms or by the increase of relaxed or linear DNA forms after oxidative attack. The UV spectrum study showed that verbascoside can form complexes with Fe(II) or Fe(III), and the complexation can be reversed by the addition of EDTA. The formation constants of verbascoside-Fe complexes were estimated as 10(21.03) and 10(31.94) M(-2) for Fe(II) and Fe(III) respectively. The inhibition of Fenton reaction by verbascoside could be partially explained by the sequestration of Fe ions.
Assuntos
Antioxidantes/farmacologia , Dano ao DNA , Glucosídeos/farmacologia , Ferro/metabolismo , Fenóis/farmacologia , Glucosídeos/metabolismo , Radical Hidroxila , Fenóis/metabolismoRESUMO
A new spectral code that can be used by Relational Database Management Systems (RDBMS) as an index for infrared (IR) spectra searches in Relational Database (RDB) is presented and its suitability is evaluated. Spectral codes are constructed for all spectra in the database as the spectral indexes and three query strings are created with the same theory used for the creation of the index code for the query spectrum. Some effects of parameters used to create index strings and query strings are discussed. All spectral searches are accomplished in structured query language (SQL) approach and the utilization examples of SQL have been shown. The sequential application of this procedure can reduce the original library of about 18000 spectra to a few spectra that can be used as references for subsequent detailed comparison. The software developed for the proposed system is particularly suitable for spectral search and structure interpretation.
Assuntos
Sistemas de Gerenciamento de Base de Dados , Bases de Dados Factuais , Armazenamento e Recuperação da Informação/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , AlgoritmosRESUMO
It is well known that cell surface carbohydrates play a role in cell-cell adhesion and communication. LewisX glycosphingolipids form microdomains on cell surfaces. Homotypic and calcium-mediated LewisX-LewisX (LeX-LeX) interactions were proposed to be responsible for the initial steps of cell adhesion, and to mediate embryogenesis and metastasis. Various techniques have been used to investigate such interactions, but little information is available on the geometry and the mechanism of dimerisation. To better understand these interactions, a new molecular model was developed to simulate homotypic interactions in explicit solvent with and without calcium ions. Accurate analysis of both trajectories yielded valuable information about the energetics of LeX-LeX dimerisation. Detailed interpretation of the hydrogen bond network and the presence of calcium ions along the trajectory provide valuable insights into the role of calcium ions in this carbohydrate-carbohydrate interaction.
Assuntos
Antígenos do Grupo Sanguíneo de Lewis/química , Antígenos CD15/química , Cálcio/química , Adesão Celular , Comunicação Celular , Simulação por Computador , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Termodinâmica , Trissacarídeos/químicaRESUMO
On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A(1), NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure-activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A(12)), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A(12) could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.
Assuntos
Fármacos Anti-HIV/química , Química Farmacêutica/métodos , Proteína gp41 do Envelope de HIV/química , Inibidores da Fusão de HIV/farmacologia , Pirróis/química , Animais , Antivirais/química , Antivirais/farmacologia , Desenho de Fármacos , Inibidores da Fusão de HIV/química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estrutura Secundária de Proteína , Relação Estrutura-AtividadeRESUMO
We introduce the principles and the architecture of a user-friendly software named MOLDIA (Molecular Diversity Analysis) which aims to the comparison of diverse molecular data sets through an XML structured database of predefined fragments. The MOLDIA descriptors are composed of complex fingerprint-like structures, which enclose not only structural information but also physicochemical property data. The system architecture includes the use of customizable weights on molecular descriptors and different choices of similarity/diversity measures to analyze the given data sets. Intermolecular comparisons using Ullmann's algorithm were optimized by the use of fuzzy logic, generic atoms, and a whole system of chemical graph analysis. We have found that customizing the similarity/diversity computation using structural and/or properties weights and choosing the level of fuzziness of the molecular comparison allow the user to adapt the tool to particular needs and increases the possibilities of MolDiA applications. The implementation of XML Web technologies has proven to improve and ease the extraction, processing, and analysis of chemical information.
Assuntos
Software , Computadores , Estrutura MolecularRESUMO
The gene expression programming, a novel machine learning algorithm, is used to develop quantitative model as a potential screening mechanism for a series of 1,4-dihydropyridine calcium channel antagonists for the first time. The heuristic method was used to search the descriptor space and select the descriptors responsible for activity. A nonlinear, six-descriptor model based on gene expression programming with mean-square errors 0.19 was set up with a predicted correlation coefficient (R2) 0.92. This paper provides a new and effective method for drug design and screening.
Assuntos
Inteligência Artificial , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Algoritmos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Expressão Gênica , Relação Quantitativa Estrutura-AtividadeRESUMO
This review is dedicated to a survey on molecular similarity and diversity. Key findings reported in recent investigations are selectively highlighted and summarized. Even if this overview is mainly centered in chemoinformatics, applications in other areas (pharmaceutical and medical chemistry, combinatorial chemistry, chemical databases management, etc.) are also introduced. The approaches used to define and describe the concepts of molecular similarity and diversity in the context of chemoinformatics are discussed in the first part of this review. We introduce, in the second and third parts, the descriptions and analyses of different methods and techniques. Finally, current applications and problems are enumerated and discussed in the last part.
Assuntos
Técnicas de Química Combinatória/métodos , Desenho de Fármacos , Modelos Químicos , Algoritmos , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Estrutura MolecularRESUMO
Cantharidin is a natural toxin that possesses potent anti-tumor properties. Its clinical application, however, is limited due to severe side-effects. Its cytotoxicity is believed to be mediated by the inhibition of serine/threonine protein phosphatase 2A. In order to identify new compounds with potential clinical therapeutic use, a series of cantharidin analogues, including those with skeletal modifications at 1-C position (analogues 1-6) and those with anhydride modifications (analogues 7-13), were synthesized, and tested for their inhibitory effects on protein phosphatase 2A and their cytotoxicity to a panel of cancer cell lines. In addition, the mode of inhibition of cantharidin and analogue 13 on protein phosphatase 2A was determined by enzymatic kinetics assay. The data indicated that analogue 13 exhibited potent cytotoxicity to all cancer cell lines, and analogues 9, 11 and 12 showed relatively weak cytotoxicity to one or more cell lines, while other analogues showed little cytotoxicity. Accordingly, analogue 13 exhibited potent inhibitory activity on protein phosphatase 2A, and analogues 9, 11 and 12 showed weak inhibitory activity, while other analogues did not show any inhibitory activity. The findings indicate that the cytotoxicity of synthetic cantharidin analogues is likely to be associated with their protein phosphatase 2A inhibitory activity. The mode of inhibition of cantharidin and analogue 13 on protein phosphatase 2A is identified as noncompetitive inhibition by the Lineweaver-Burk plot.
Assuntos
Cantaridina/análogos & derivados , Cantaridina/toxicidade , Inibidores Enzimáticos/toxicidade , Fosfoproteínas Fosfatases/antagonistas & inibidores , Cantaridina/síntese química , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HL-60 , Humanos , Técnicas In Vitro , Fosfoproteínas Fosfatases/metabolismo , Proteína Fosfatase 2RESUMO
Five series totalling 51 of sinapyl alcohol derivatives were designed and synthesized. Their cytotoxicity analyses were performed on six human tumor cell lines such as PC-3, CNE, KB, A549, BEL-7404, and HeLa. Certain sinapyl alcohol derivatives showed significant cytotoxic activities. Compound 14d exhibited especially potent cytotoxicity against the BEL-7404 cell line with an IC50 value of 0.7 microM, which showed more cytotoxic activity than the positive control, cisplatin. The structure-cytotoxicity relationships were discussed and the CoMFA analysis was performed using the cytotoxic data against HeLa cells as a template.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Eletroquímica , Células HeLa , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Fenilpropionatos/síntese químicaRESUMO
Gas chromatographic retention indices of nitrogen-containing polycyclic aromatic compounds (N-PACs) have been predicted by quantitative structure-property relationship (QSPR) analysis based on heuristic method (HM) implemented in CODESSA. In order to indicate the influence of different molecular descriptors on retention indices and well understand the important structural factors affecting the experimental values, three multivariable linear models derived from three groups of different molecular descriptors were built. Moreover, each molecular descriptor in these models was discussed to well understand the relationship between molecular structures and their retention indices. The proposed models gave the following results: the square of correlation coefficient, R(2), for the models with one, two and three molecular descriptors was 0.9571, 0.9776 and 0.9846, respectively.
RESUMO
Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 microM. The rationality of the method was validated by experimental results.
Assuntos
Cânfora/análogos & derivados , Lactonas/química , Lactonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Cânfora/química , Cânfora/farmacologia , Farmacorresistência Viral , Transcriptase Reversa do HIV/antagonistas & inibidores , Modelos MolecularesRESUMO
Our current studies aimed at developing new potential anti-AIDS drug candidates have focused on the design and synthesis of new DCK analogs with improved molecular water solubility. Based on the structures and biodata of previous DCK analogs, 3D-QSAR studies have been performed which resulted in two reliable computational models, CoMFA and CoMSIA, with r(2) values of 0.995 and 0.987, and q(2) values of 0.662 and 0.657, respectively. In accord with these 3D-QSAR models, 15 new DCK analogs with polar functional groups at the 3-position were subsequently designed, synthesized, and evaluated against HIV-1 replication in H9 and MT4 cell lines. New DCK analogs 3b, 3c, 4b, 4c, 6a, 7c, and 9a showed promising potency with EC(50) values ranging from 0.09 to 0.0002 microM in both assays. Meanwhile, these promising compounds also showed a wide range of predicted logP values from 0.90 to 5.19, which increased the probability of identifying anti-HIV drug candidates from this class of compounds for clinical trials. Furthermore, both experimental and predicted values matched well, corroborating the reliability of the established 3D-QSAR models.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cumarínicos/síntese química , Cumarínicos/farmacologia , Desenho de Fármacos , Fármacos Anti-HIV/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular , Cumarínicos/química , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Modelos Químicos , Modelos Moleculares , Relação Quantitativa Estrutura-AtividadeRESUMO
Baogongteng A (BGT-A), a naturally occurring tropane muscarinic agonist isolated from Chinese medicinal plant, exhibits a bioactive effect different from those of many tropane alkaloids that are muscarinic antagonists. A series of racemic derivatives of BGT-A was synthesized to study the structure-activity relationships (SAR). To explore further the SAR in this series and to ultimately design muscarinic agonists for drug development, a Comparative Molecular Field Analysis (CoMFA) was performed. The values of the leave-one-out cross-validated correlation coefficient q2 and the conventional correlation coefficient r2 for the model are 0.613 and 0.965, respectively. The regression analysis of the data indicated that the steric effect of N-substituted group on tropane of analyzed compounds critically affected the agonistic activity to muscarinic receptors.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Agonistas Muscarínicos/síntese química , Relação Quantitativa Estrutura-Atividade , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cobaias , Modelos Moleculares , Agonistas Muscarínicos/farmacologia , Músculo Esquelético/química , Extratos Vegetais , Ligação Proteica , Receptores Muscarínicos/química , Receptores Muscarínicos/metabolismo , Tropanos/síntese química , Tropanos/farmacologiaRESUMO
Multiple linear regression (MLR) based on forward stepwise multiple regression techniques was used for predicting gas chromatographic retention index of sulfides after calculating their quantum-chemical parameters. The correlative quantitative model between the retention index (IR) of sulfides on four stationary phases of different polarities and their quantum chemical parameters was built. The results proved the strong predictive power of the models. The root-mean-square error (RMS) of the regression equation was less than 4%.
RESUMO
The active site of 3CL proteinase (3CLpro) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with 3CLpro of human coronavirus, then it was selected as the reference for molecular docking and database screening. The ligands from two databases were used to search potential lead structures with molecular docking. Several structures from natural products and ACD-SC databases were found to have lower binding free energy with 3CLpro than that of Ag7088. These structures have similar hydrophobicity to Ag7088. They have complementary electrostatic potential and hydrogen bond acceptor and donor with 3CLpro, showing that the strategy of anti-SARS drug design based on molecular docking and database screening is feasible.