Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Theranostics ; 11(16): 8092-8111, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335982

RESUMO

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.


Assuntos
Proteína Tirosina Quinase CSK/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Membrana/metabolismo , Proteína Tirosina Quinase CSK/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Genes src/genética , Genes src/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Peptídeos/metabolismo , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Tetraspaninas/genética , Tetraspaninas/metabolismo
2.
J Mol Model ; 26(8): 207, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32676810

RESUMO

Colorectal cancer, which is considered one of the leading causes of mortality worldwide, develops through the formation of benign polyps on the inner colon or rectum wall. Truncations in adenomatous polyposis coli (APC) gene lead to the spread of the disease in the entire colon region when combined with the guanine nucleotide exchange factor (GEF) Asef. A series of peptidomimetic agents were previously discovered as protein-protein interaction inhibitors that can target the APC-Asef interface. Structure-based virtual screening (SBVS), using a set of docking methods combined with molecular dynamics simulations, was carried out to identify new small drug-like agents. After the initial screening process, compounds with diverse chemical scaffolds and direct interaction with Arg549 and other active site residues were chosen and subjected to induce fit. The amide functional group found in the ligand hit structures showed strong interactions with Arg549, leading to observable conformational changes that allow suitable positioning within the peptide binding site. Furthermore, the pH-specific MD simulations of the top hit 838 within the APC-Asef binding site depicted significant interactions required for biochemical recognition in changing microenvironment. Predicted inhibitory constant (Ki) values and binding free energies of hits further described the significance of the amide group over the other chemical scaffolds. This combination of in silico approaches provides key insights for colorectal drug discovery programs targeting the APC-Asef interaction. Graphical abstract The common active site residues involved in interaction with ligands.

3.
Molecules ; 25(3)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033144

RESUMO

Tuberculosis (TB) remains a serious threat to global public health, responsible for an estimated 1.5 million mortalities in 2018. While there are available therapeutics for this infection, slow-acting drugs, poor patient compliance, drug toxicity, and drug resistance require the discovery of novel TB drugs. Discovering new and more potent antibiotics that target novel TB protein targets is an attractive strategy towards controlling the global TB epidemic. In silico strategies can be applied at multiple stages of the drug discovery paradigm to expedite the identification of novel anti-TB therapeutics. In this paper, we discuss the current TB treatment, emergence of drug resistance, and the effective application of computational tools to the different stages of TB drug discovery when combined with traditional biochemical methods. We will also highlight the strengths and points of improvement in in silico TB drug discovery research, as well as possible future perspectives in this field.


Assuntos
Antituberculosos/farmacologia , Desenho de Fármacos , Descoberta de Drogas/métodos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Teoria da Densidade Funcional , Farmacorresistência Bacteriana , Humanos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade
4.
J Med Chem ; 62(17): 8011-8027, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411468

RESUMO

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of ß-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminoaciltransferases/antagonistas & inibidores , Ansiolíticos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Doença de Alzheimer/metabolismo , Aminoaciltransferases/metabolismo , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Teoria Quântica , Relação Estrutura-Atividade
5.
Curr Opin Struct Biol ; 55: 147-153, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31102980

RESUMO

Demand for novel GPCR modulators is increasing as the association between the GPCR signaling pathway and numerous diseases such as cancers, psychological and metabolic disorders continues to be established. In silico structure-based drug design (SBDD) offers an outlet where researchers could exploit the accumulating structural information of GPCR to expedite the process of drug discovery. The coupling of structure-based approaches such as virtual screening and molecular docking with molecular dynamics and/or Monte Carlo simulation aids in reflecting the dynamics of proteins in nature into previously static docking studies, thus enhancing the accuracy of rationally designed ligands. This review will highlight recent computational strategies that incorporate protein flexibility into SBDD of GPCR-targeted ligands.


Assuntos
Receptores Acoplados a Proteínas G/química , Sítio Alostérico , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Conformação Proteica
6.
Cell Metab ; 29(6): 1306-1319.e7, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30956113

RESUMO

The mechanistic target of rapamycin complex (mTORC1) is a signaling hub on the lysosome surface, responding to lysosomal amino acids. Although arginine is metabolically important, the physiological arginine sensor that activates mTOR remains unclear. Here, we show that transmembrane 4 L six family member 5 (TM4SF5) translocates from plasma membrane to lysosome upon arginine sufficiency and senses arginine, culminating in mTORC1/S6K1 activation. TM4SF5 bound active mTOR upon arginine sufficiency and constitutively bound amino acid transporter SLC38A9. TM4SF5 binding to the cytosolic arginine sensor Castor1 decreased upon arginine sufficiency, thus allowing TM4SF5-mediated sensing of metabolic amino acids. TM4SF5 directly bound free L-arginine via its extracellular loop possibly for the efflux, being supported by mutant study and homology and molecular docking modeling. Therefore, we propose that lysosomal TM4SF5 senses and enables arginine efflux for mTORC1/S6K1 activation, and arginine-auxotroph in hepatocellular carcinoma may be targeted by blocking the arginine sensing using anti-TM4SF5 reagents.


Assuntos
Arginina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Membrana/fisiologia , Animais , Arginina/química , Transporte Biológico , Células Cultivadas , Células HEK293 , Células Hep G2 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/química , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Quaternária de Proteína , Transdução de Sinais/genética
7.
J Agric Food Chem ; 66(40): 10608-10616, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30251539

RESUMO

Curcumin is a yellow-colored ingredient in dietary spice turmeric ( Curcuma longa Linn). This nontoxic polyphenol has antitumor, anti-inflammatory, apoptotic, and antioxidant activities. The ingested curcumin is reduced to multihydrated forms with more potent therapeutic potentials by the curcumin reductase (CurA) from commensal Escherichia coli. In this study, we demonstrated that Vibrio vulnificus CurA ( VvCurA) with 87% sequence similarity to the E. coli CurA exhibits the curcumin-reducing activity through spectrophotometric detection of NADPH oxidation and high performance liquid chromatographic analysis of curcumin consumption and product generation. Afterward, we determined the crystal structures of VvCurA and the VvCurA/NADPH complex, and made the in silico model of the VvCurA/NADPH/curcumin ternary complex through induced fit docking. Based on structural information, active site residues that play critical roles in catalysis have been identified and characterized by mutational and kinetic studies, leading us to propose the reaction mechanism of CurA.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Curcumina/metabolismo , Oxirredutases/química , Oxirredutases/metabolismo , Vibrio vulnificus/enzimologia , Proteínas de Bactérias/genética , Biocatálise , Domínio Catalítico , Curcumina/química , Cinética , Simulação de Acoplamento Molecular , NADP/metabolismo , Oxirredutases/genética , Vibrio vulnificus/química , Vibrio vulnificus/genética
8.
Molecules ; 23(8)2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082644

RESUMO

The advent of advanced molecular modeling software, big data analytics, and high-speed processing units has led to the exponential evolution of modern drug discovery and better insights into complex biological processes and disease networks. This has progressively steered current research interests to understanding protein-protein interaction (PPI) systems that are related to a number of relevant diseases, such as cancer, neurological illnesses, metabolic disorders, etc. However, targeting PPIs are challenging due to their "undruggable" binding interfaces. In this review, we focus on the current obstacles that impede PPI drug discovery, and how recent discoveries and advances in in silico approaches can alleviate these barriers to expedite the search for potential leads, as shown in several exemplary studies. We will also discuss about currently available information on PPI compounds and systems, along with their usefulness in molecular modeling. Finally, we conclude by presenting the limits of in silico application in drug discovery and offer a perspective in the field of computer-aided PPI drug discovery.


Assuntos
Descoberta de Drogas , Humanos , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Peptidomiméticos/química , Ligação Proteica
9.
Drug Des Devel Ther ; 11: 563-574, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28280303

RESUMO

Computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. The enzyme 7,8-diaminopelargonic acid aminotransferase (BioA) in Mycobacterium tuberculosis (Mtb), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. The computational screening of 4.5 million compounds from the Enamine REAL database has ultimately yielded 45 high-scoring, high-affinity compounds with desirable in silico absorption, distribution, metabolism, excretion, and toxicity properties. Seventeen of the 45 compounds were subjected to bioactivity validation using the resazurin microtiter assay. Among the 4 actives, compound 7 ((Z)-N-(2-isopropoxyphenyl)-2-oxo-2-((3-(trifluoromethyl)cyclohexyl)amino)acetimidic acid) displayed inhibitory activity up to 83% at 10 µg/mL concentration against the growth of the Mtb H37Ra strain.


Assuntos
Antibacterianos/farmacologia , Simulação por Computador , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Transaminases/antagonistas & inibidores , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Relação Estrutura-Atividade , Transaminases/metabolismo
10.
Drug Des Devel Ther ; 10: 1147-57, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27042006

RESUMO

Mycobacterium tuberculosis (Mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. It is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. One such target is the enzyme l,d-transpeptidase 2, also known as LdtMt2, a protein primarily responsible for the catalysis of 3→3 cross-linkages that make up the mycolyl-arabinogalactan-peptidoglycan complex of Mtb. In this study, structure-based pharmacophore screening, molecular docking, and in silico toxicity evaluations were employed in screening compounds from a database of synthetic compounds. Out of the 4.5 million database compounds, 18 structures were identified as high-scoring, high-binding hits with very satisfactory absorption, distribution, metabolism, excretion, and toxicity properties. Two out of the 18 compounds were further subjected to in vitro bioactivity assays, with one exhibiting a good inhibitory activity against the Mtb H37Ra strain.


Assuntos
Antituberculosos/farmacologia , Simulação por Computador , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Peptidil Transferases/antagonistas & inibidores , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Peptidil Transferases/metabolismo , Relação Estrutura-Atividade
11.
Arch Pharm Res ; 38(9): 1686-701, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26208641

RESUMO

Drug discovery utilizes chemical biology and computational drug design approaches for the efficient identification and optimization of lead compounds. Chemical biology is mostly involved in the elucidation of the biological function of a target and the mechanism of action of a chemical modulator. On the other hand, computer-aided drug design makes use of the structural knowledge of either the target (structure-based) or known ligands with bioactivity (ligand-based) to facilitate the determination of promising candidate drugs. Various virtual screening techniques are now being used by both pharmaceutical companies and academic research groups to reduce the cost and time required for the discovery of a potent drug. Despite the rapid advances in these methods, continuous improvements are critical for future drug discovery tools. Advantages presented by structure-based and ligand-based drug design suggest that their complementary use, as well as their integration with experimental routines, has a powerful impact on rational drug design. In this article, we give an overview of the current computational drug design and their application in integrated rational drug development to aid in the progress of drug discovery research.


Assuntos
Desenho Assistido por Computador , Desenho de Fármacos , Descoberta de Drogas/métodos , Preparações Farmacêuticas/síntese química , Animais , Humanos , Preparações Farmacêuticas/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...