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1.
Anticancer Agents Med Chem ; 21(14): 1901-1910, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33292143

RESUMO

BACKGROUND: Triple-negative BC is the most aggressive type of breast cancer and its lack of responsiveness to conventional therapies requires screening of new chemical entities. Anti-migratory compounds are promising to treat metastatic cancer since they inhibit one of the main steps of the metastatic cascade. Spirocyclic compounds are non-conventional structures used as building blocks for the synthesis of biologically active molecules and considered interesting structures in the search for new targets in cancer research. OBJECTIVE: Here, we evaluated the potential of eight synthetic spirocyclohexadienones as cell migration inhibitors. METHODS: The anti-migratory ability of compounds was tested by wound healing and Boyden chamber approaches. Experiments in tubulin were performed by fluorescence and tubulin polymerization techniques. Finally, compounds were submitted to cell proliferation inhibition and flow cytometry assays to explore the mechanism by which they inhibit cell migration. RESULTS: Four compounds inhibited cell migration significantly. Analogs containing the 3,4,5-trimethoxyphenil ring at R1 position were the most potent and, thus, selected for additional experiments. Tubulin polymerization and fluorescence assays highlighted a possible binding of spirocyclohexadienones in the colchicine binding site; however, these compounds did not affect the cell cycle to the same extent as colchicine. Cell proliferation was affected and, notably, the most potent analogs induced apoptosis of tumor cells, suggesting a different mechanism by which they inhibit cell migration. CONCLUSION: We presented, for the first time, a series of eight synthetic spirocyclohexadienones with the ability to inhibit TNBC cell migration. These compounds represent a new category to be explored as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Cicloexenos/farmacologia , Compostos de Espiro/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cicloexenos/síntese química , Cicloexenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Neoplasias de Mama Triplo Negativas/patologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
2.
Proteins ; 88(4): 625-632, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31693206

RESUMO

The analysis of amino acid coevolution has emerged as a practical method for protein structural modeling by providing structural contact information from alignments of amino acid sequences. In parallel, chemical cross-linking/mass spectrometry (XLMS) has gained attention as a universally applicable method for obtaining low-resolution distance constraints to model the quaternary arrangements of proteins, and more recently even protein tertiary structures. Here, we show that the structural information obtained by XLMS and coevolutionary analysis are effectively complementary: the distance constraints obtained by each method are almost exclusively associated with non-coincident pairs of residues, and modeling results obtained by the combination of both sets are improved relative to considering the same total number of constraints of a single type. The structural rationale behind the complementarity of the distance constraints is discussed and illustrated for a representative set of proteins with different sizes and folds.


Assuntos
Aminoácidos/química , Coevolução Biológica , Proteínas/química , Sequência de Aminoácidos , Reagentes de Ligações Cruzadas , Humanos , Espectrometria de Massas , Modelos Moleculares , Dobramento de Proteína , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas/fisiologia , Relação Estrutura-Atividade , Termodinâmica
3.
Methods Mol Biol ; 1762: 31-50, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29594766

RESUMO

Drug discovery has evolved significantly over the past two decades. Progress in key areas such as molecular and structural biology has contributed to the elucidation of the three-dimensional structure and function of a wide range of biological molecules of therapeutic interest. In this context, the integration of experimental techniques, such as X-ray crystallography, and computational methods, such as molecular docking, has promoted the emergence of several areas in drug discovery, such as structure-based drug design (SBDD). SBDD strategies have been broadly used to identify, predict and optimize the activity of small molecules toward a molecular target and have contributed to major scientific breakthroughs in pharmaceutical R&D. This chapter outlines molecular docking and structure-based virtual screening (SBVS) protocols used to predict the interaction of small molecules with the phosphatidylinositol-bisphosphate-kinase PI3Kδ, which is a molecular target for hematological diseases. A detailed description of the molecular docking and SBVS procedures and an evaluation of the results are provided.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/química , Cristalografia por Raios X , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Conformação Proteica , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
4.
Bioinformatics ; 34(13): 2201-2208, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29447388

RESUMO

Motivation: Elucidation of protein native states from amino acid sequences is a primary computational challenge. Modern computational and experimental methodologies, such as molecular coevolution and chemical cross-linking mass-spectrometry allowed protein structural characterization to previously intangible systems. Despite several independent successful examples, data from these distinct methodologies have not been systematically studied in conjunction. One challenge of structural inference using coevolution is that it is limited to sequence fragments within a conserved and unique domain for which sufficient sequence datasets are available. Therefore, coupling coevolutionary data with complimentary distance constraints from orthogonal sources can provide additional precision to structure prediction methodologies. Results: In this work, we present a methodology to combine residue interaction data obtained from coevolutionary information and cross-linking/mass spectrometry distance constraints in order to identify functional states of proteins. Using a combination of structure-based models (SBMs) with optimized Gaussian-like potentials, secondary structure estimation and simulated annealing molecular dynamics, we provide an automated methodology to integrate constraint data from diverse sources in order to elucidate the native conformation of full protein systems with distinct complexity and structural topologies. We show that cross-linking mass spectrometry constraints improve the structure predictions obtained from SBMs and coevolution signals, and that the constraints obtained by each method have a useful degree of complementarity that promotes enhanced fold estimates. Availability and implementation: Scripts and procedures to implement the methodology presented herein are available at https://github.com/mcubeg/DCAXL. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Espectrometria de Massas/métodos , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína , Análise de Sequência de Proteína/métodos , Sequência de Aminoácidos , Reagentes de Ligações Cruzadas , Dobramento de Proteína
5.
Sci Rep ; 5: 13652, 2015 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-26338201

RESUMO

We develop a procedure to characterize the association of protein structures into homodimers using coevolutionary couplings extracted from Direct Coupling Analysis (DCA) in combination with Structure Based Models (SBM). Identification of dimerization contacts using DCA is more challenging than intradomain contacts since direct couplings are mixed with monomeric contacts. Therefore a systematic way to extract dimerization signals has been elusive. We provide evidence that the prediction of homodimeric complexes is possible with high accuracy for all the cases we studied which have rich sequence information. For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively. This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation. The identification of dimeric complexes can provide interesting molecular insights in the construction of large oligomeric complexes and be useful in the study of aggregation related diseases like Alzheimer's or Parkinson's.


Assuntos
Dimerização , Evolução Molecular , Modelos Genéticos , Simulação de Acoplamento Molecular , Proteínas/química , Proteínas/genética , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação/genética , Simulação por Computador , Dados de Sequência Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Complexos Multiproteicos/ultraestrutura , Ligação Proteica/genética , Conformação Proteica , Proteínas/ultraestrutura , Análise de Sequência de Proteína/métodos
6.
Molecules ; 20(7): 13384-421, 2015 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-26205061

RESUMO

Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure- and ligand-based methods.


Assuntos
Desenho de Fármacos , Simulação de Acoplamento Molecular/métodos , Animais , Humanos , Relação Estrutura-Atividade
7.
J Chem Inf Model ; 53(9): 2390-401, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-23889525

RESUMO

Mycobacterium tuberculosis InhA (MtInhA) is an attractive enzyme to drug discovery efforts due to its validation as an effective biological target for tuberculosis therapy. In this work, two different virtual-ligand-screening approaches were applied in order to identify new InhA inhibitors' candidates from a library of ligands selected from the ZINC database. First, a 3-D pharmacophore model was built based on 36 available MtInhA crystal structures. By combining structure-based and ligand-based information, four pharmacophoric points were designed to select molecules able to satisfy the binding features of MtInhA substrate-binding cavity. The second approach consisted of using four well established docking programs, with different search algorithms, to compare the binding mode and score of the selected molecules from the aforementioned library. After detailed analyses of the results, six ligands were selected for in vitro analysis. Three of these molecules presented a satisfactory inhibitory activity with IC50 values ranging from 24 (±2) µM to 83 (±5) µM. The best compound presented an uncompetitive inhibition mode to NADH and 2-trans-dodecenoyl-CoA substrates, with Ki values of 24 (±3) µM and 20 (±2) µM, respectively. These molecules were not yet described as antituberculars or as InhA inhibitors, making its novelty interesting to start efforts on ligand optimization in order to identify new effective drugs against tuberculosis having InhA as a target. More studies are underway to dissect the discovered uncompetitive inhibitor interactions with MtInhA.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia , Oxirredutases/antagonistas & inibidores , Interface Usuário-Computador , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Ligantes , Oxirredutases/química , Oxirredutases/metabolismo , Conformação Proteica
8.
J Nat Prod ; 76(3): 439-44, 2013 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-23330984

RESUMO

We describe herein the design and development of an innovative tool called the NuBBE database (NuBBEDB), a new Web-based database, which incorporates several classes of secondary metabolites and derivatives from the biodiversity of Brazil. This natural product database incorporates botanical, chemical, pharmacological, and toxicological compound information. The NuBBEDB provides specialized information to the worldwide scientific community and can serve as a useful tool for studies on the multidisciplinary interfaces related to chemistry and biology, including virtual screening, dereplication, metabolomics, and medicinal chemistry. The NuBBEDB site is at http://nubbe.iq.unesp.br/nubbeDB.html .


Assuntos
Biodiversidade , Produtos Biológicos , Brasil , Bases de Dados Factuais , Internet , Estrutura Molecular
9.
Med Chem ; 7(3): 155-64, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21486209

RESUMO

Migrastatin, a macrolide natural product, and its structurally related analogs are potent inhibitors of cancer cell metastasis, invasion and migration. In the present work, a specialized fragment-based method was employed to develop QSAR models for a series of migrastatin and isomigrastatin analogs. Significant correlation coefficients were obtained (best model, q2 = 0.76 and r2 = 0.91) indicating that the QSAR models possess high internal consistency. The best model was then used to predict the potency of an external test set, and the predicted values were in good agreement with the experimental results (R2 pred = 0.85). The final model and the corresponding contribution maps, combined with molecular modeling studies, provided important insights into the key structural features for the anticancer activity of this family of synthetic compounds based on natural products.


Assuntos
Macrolídeos/química , Macrolídeos/farmacologia , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Piperidonas/química , Piperidonas/farmacologia , Relação Quantitativa Estrutura-Atividade , Movimento Celular/efeitos dos fármacos , Bases de Dados Factuais , Macrolídeos/síntese química , Modelos Moleculares , Conformação Molecular , Invasividade Neoplásica , Piperidonas/síntese química , Estereoisomerismo
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