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










Base de dados
Intervalo de ano de publicação
1.
J Enzyme Inhib Med Chem ; 34(1): 1573-1589, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852269

RESUMO

Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 µM, 1.3 µM, 1.4 µM, 107 nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 µM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridazinas/síntese química , Piridazinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Sci Rep ; 9(1): 12392, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455818

RESUMO

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed. In this work, we report the rigorous and systematic in vitro characterization of a selected set of potent PD-1/PD-L1 macrocyclic peptide (BMSpep-57) and small-molecule inhibitors (BMS-103, BMS-142) from BMS and a peptidomimetic small-molecule inhibitor from Aurigene (Aurigene-1) using a series of biochemical and cell-based assays. Our results confirm that BMS-103 and BMS-142 are strongly active in biochemical assays; however, their acute cytotoxicity greatly compromised their immunological activity. On the other hand, Aurigene-1 did not show any activity in both biochemical and immunological assays. Furthermore, we also report the discovery of a small-molecule immune modulator, whose mode-of-action is not clear; however, it exhibits favorable drug-like properties and strong immunological activity. We hope that the results presented here will be useful in guiding the development of next-generation PD-1/PD-L1 small molecule inhibitors.

3.
J Mol Graph Model ; 90: 128-143, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31082639

RESUMO

The recurrent outbreaks of dengue virus around the globe represent a huge challenge for governments and public health organizations. With the rapid growth and ease of transportation, dengue disease continues to spread, placing more of the world population under constant threat. Despite decades of research efforts, no effective small molecule antivirals are available against dengue virus. With the efficacy of the recently developed vaccine to be determined, there is an urgent unmet need for small molecule dengue virus treatments. In the current study, we employed state-of-the-art molecular modelling simulations to identify novel inhibitors of the dengue virus envelope protein. The binding modes of all compounds within the conserved ß-OctylGlucoside (ß-OG) pocket were studied using a combination of docking, molecular dynamics simulations and binding free energy calculations. Here, we describe ten new compounds that significantly reduce production of dengue virus as determined using standard cell-based virological assays. Moreover, we present a comprehensive structural analysis of the identified hits, focusing on their electrostatic and lipophilic binding energy contributions. Finally, we highlight the effect of the desolvation penalty in limiting the activity of some of these compounds. The data presented here paves the way toward rationally designing selective and potent novel inhibitors against dengue virus.

4.
Bioorg Chem ; 82: 340-359, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30428414

RESUMO

VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 µM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Indazóis/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Caspase 3/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Drogas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Termodinâmica , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
PLoS One ; 13(2): e0191905, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29444113

RESUMO

The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research. In this work, we present the structural and mechanistic details of potassium ion permeation through an open KCNQ1 structural model using the combined molecular dynamics and steered molecular dynamics simulations. We discuss the processes and key residues involved in the permeation of a potassium ion through the KCNQ1 ion channel, and how the ion permeation is affected by (i) the KCNQ1-KCNE1 interactions and (ii) the binding of chromanol 293B ligand and its derivatives into the complex. The results reveal that interactions between KCNQ1 with KCNE1 causes a pore constriction in the former, which in-turn forms small energetic barriers in the ion-permeation pathway. These findings correlate with the previous experimental reports that interactions of KCNE1 dramatically slows the activation of KCNQ1. Upon ligand-binding onto the complex, the energy-barriers along ion permeation path are more pronounced, as expected, therefore, requiring higher force in our steered-MD simulations. Nevertheless, pulling the ion when a weak blocker is bound to the channel does not necessitate high force in SMD. This indicates that our SMD simulations have been able to discern between strong and week blockers and reveal their influence on potassium ion permeation. The findings presented here will have some implications in understanding the potential off-target interactions of the drugs with the KCNQ1/KCNE1 channel that lead to cardiotoxic effects.


Assuntos
Canal de Potássio KCNQ1/metabolismo , Humanos , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica
6.
J Mol Graph Model ; 78: 26-47, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28992529

RESUMO

The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (IKs) current in the heart, which plays an important role in heart signaling. The importance of KCNQ1/KCNE1 channel's function is further implicated by the linkage between loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1, and long QT syndromes, congenital atrial fibrillation, and short QT syndrome. Also, KCNQ1/KCNE1 channels are an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities. One solution to address and study the mentioned aspects of KCNQ1/KNCE1 channel would be the structural studies using a validated and accurate model. Along the same line in this study, we have used several top-notch modeling approaches to build a structural model for the open state of KCNQ1 protein, which is both accurate and compatible with available experimental data. Next, we included the KCNE1 protein components using data-driven protein-protein docking simulations, encompassing a 4:2 stoichiometry to complete the picture of the channel complex formed by these two proteins. All the protein systems generated through these processes were refined by long Molecular Dynamics simulations. The refined models were analyzed extensively to infer data about the interaction of KCNQ1 channel with its accessory KCNE1 beta subunits.


Assuntos
Canais Iônicos/química , Canal de Potássio KCNQ1/química , Miocárdio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/química , Humanos , Canais Iônicos/genética , Canal de Potássio KCNQ1/genética , Modelos Estruturais , Simulação de Dinâmica Molecular , Mutação , Miocárdio/química , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Mapas de Interação de Proteínas
7.
J Mol Model ; 23(11): 308, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-29019005

RESUMO

Applying atomistic computational modeling to drug discovery has proven to be a hugely successful approach, allowing drug-receptor interactions to be predicted and drugs to be optimized for potency, selectivity, and safety. However, when it comes to predicting protein-protein interactions and to rationally designing regulators of these interactions, computational tools often fail. Here, we report one of the rare instances where state-of-the-art computer simulations, guided by experiment, were able to correctly predict one of the most sophisticated protein-protein interactions. We revisit our previous discovery of the complex of human PD-1 with the ligand PD-L1 and compare our earlier findings with the recently published crystal structure of the same complex. Side-by-side comparison of the model of the complex with its crystal structure reveals outstanding agreement and suggests that our protein-protein prediction workflow could be applied to similar problems.


Assuntos
Antígeno B7-H1/metabolismo , Simulação por Computador , Descoberta de Drogas/métodos , Modelos Moleculares , Receptor de Morte Celular Programada 1/metabolismo , Mapeamento de Interação de Proteínas/métodos , Antígeno B7-H1/química , Biologia Computacional/métodos , Humanos , Ligantes , Receptor de Morte Celular Programada 1/química
8.
Biochemistry ; 56(40): 5428-5439, 2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28898057

RESUMO

In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ligand PD-L1. We studied the conformational dynamics of PD-L1 through principal component analysis of existing crystal structures combined with classical and accelerated molecular dynamics simulations. We identified the maximum structural displacements that take place in all PD-L1 crystal structures and in the molecular dynamics trajectories. We found that these displacements are attributed to specific flexible regions in the protein. We also investigated the conformational preference for small molecule binding and highlighted a methionine residue at the binding site, which plays a key role in drug binding. The binding mechanism of PD-L1 to other binding partners is also discussed in detail from a computational perspective. We hope that the data presented here support the ongoing efforts to discover effective therapies targeting the PD-1 immune-checkpoint pathway.


Assuntos
Antígeno B7-H1/química , Antígeno B7-H1/metabolismo , Sítios de Ligação , Desenho de Drogas , Espaço Extracelular/metabolismo , Humanos , Metionina/metabolismo , Simulação de Dinâmica Molecular , Domínios Proteicos
9.
Drug Des Devel Ther ; 11: 2301-2324, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28831242

RESUMO

Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel's selectivity filters to reach the channel's central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed "state-of-the-art" steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure-property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.


Assuntos
Modelos Anatômicos , Simulação de Dinâmica Molecular , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Sítios de Ligação , Desenho de Drogas , Humanos , Canal de Sódio Disparado por Voltagem NAV1.5/química , Permeabilidade , Sódio/metabolismo , Eletricidade Estática
10.
ACS Infect Dis ; 2(11): 872-881, 2016 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-27933783

RESUMO

Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (∼picomolar IC50) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete. This is simply due to the vast complexity of cocrystallizing DCV with NS5A in the absence of two amphipathic helices that are required for DCV binding. In this context, computational modeling provides a unique alternative to solve this problem. Here, we build upon our recent discovery of a completely symmetrical interaction between DCV and NS5A and investigate the mode of binding of six other structures similar to DCV. The selected compounds include both symmetric and asymmetric molecules. In addition, we show that our model correlates very well with mutations that can confer resistance to DCV. The current study enhances our understanding of the mode of action of this class of HCV inhibitors and helps in defining the origin of resistance to these drugs.


Assuntos
Antivirais/química , Hepacivirus/efeitos dos fármacos , Imidazóis/química , Fosfoproteínas/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Biologia Computacional , Farmacorresistência Viral , Genótipo , Hepacivirus/química , Hepacivirus/genética , Hepacivirus/fisiologia , Hepatite C/virologia , Humanos , Imidazóis/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
11.
J Phys Chem A ; 119(39): 9986-95, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26344652

RESUMO

Soft X-ray photoelectron spectroscopy has been used to investigate the radiosensitizer nimorazole and related model compounds. We report the valence and C, N, and O 1s photoemission spectra and K-edge NEXAFS spectra of gas-phase nimorazole, 1-methyl-5-nitroimidazole, and 4(5)-nitroimidazole in combination with theoretical calculations. The valence band and core level spectra are in agreement with theory. We determine the equilibrium populations of the two tautomers in 4(5)-nitroimidazole and find a ratio of 1:0.7 at 390 K. The NEXAFS spectra of the studied nitroimidazoles show excellent agreement with spectra of compounds available in the literature that exhibit a similar chemical environment. By comparing 1-methyl-5-nitroimidazole (single tautomer) with 4(5)-nitroimidazole, we are able to disentangle the photoemission and photoabsorption spectra and identify features due to each single tautomer.


Assuntos
Modelos Teóricos , Nimorazol/química , Espectroscopia Fotoeletrônica/métodos , Radiossensibilizantes/química , Modelos Moleculares , Estrutura Molecular
12.
J Mol Graph Model ; 62: 105-117, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26407139

RESUMO

Entropy of binding constitutes a major, and in many cases a detrimental, component of the binding affinity in biomolecular interactions. While the enthalpic part of the binding free energy is easier to calculate, estimating the entropy of binding is further more complicated. A precise evaluation of entropy requires a comprehensive exploration of the complete phase space of the interacting entities. As this task is extremely hard to accomplish in the context of conventional molecular simulations, calculating entropy has involved many approximations. Most of these golden standard methods focused on developing a reliable estimation of the conformational part of the entropy. Here, we review these methods with a particular emphasis on the different techniques that extract entropy from atomic fluctuations. The theoretical formalisms behind each method is explained highlighting its strengths as well as its limitations, followed by a description of a number of case studies for each method. We hope that this brief, yet comprehensive, review provides a useful tool to understand these methods and realize the practical issues that may arise in such calculations.


Assuntos
Modelos Moleculares , Simulação por Computador , Entropia , Modelos Estatísticos , Conformação Molecular , Probabilidade
13.
Chem Biol Drug Des ; 86(6): 1518-27, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26212366

RESUMO

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections have been reported in Asia, Africa, and Europe. The symptoms of CHIKV infection include fever, headache, nausea, vomiting, myalgia, rash, and chronic persistent arthralgia. To date, no vaccines or selective antiviral drugs against this important emerging virus have been reported. In this study, the design, synthesis, and antiviral activity screening of new topographical peptidomimetics revealed three potential prototype agents 3a, 4b, and 5d showing 93-100% maximum inhibition of CHIKV replication in cell-based assay having EC90 of 8.76-9.57 µg/mL. Intensive molecular modeling studies including covalent docking, lowest unoccupied molecular orbital energies, and the atomic condensed Fukui functions calculations strongly suggested the covalent binding of peptidomimetics 3a, 4b, and 5d to CHIKV nsP2 protease leading to permanent enzyme inactivation via Michael adduct formation between α/ß-unsaturated ketone functionality in our designed peptidomimetics and active site catalytic cysteine1013. Furthermore, small molecular weight peptidomimetics 3a and 4b satisfied the Lipinski rule of five for drug-likeness and showed promising intestinal absorption and aqueous solubility via computational admet studies making them promising hits for further optimization.


Assuntos
Antivirais/química , Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/enzimologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Animais , Antivirais/síntese química , Domínio Catalítico , Febre de Chikungunya/tratamento farmacológico , Simulação por Computador , Desenho de Drogas , Humanos , Absorção Intestinal , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Peptidomiméticos/síntese química , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Inibidores de Proteases/síntese química , Teoria Quântica , Solubilidade , Relação Estrutura-Atividade , Células Vero
14.
J Mol Graph Model ; 57: 131-42, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25723350

RESUMO

Programmed death-1 (PD-1) is a potent inhibitory receptor of T cells which binds to two different ligands, namely PD-L1 and PD-L2, and upon binding, it inhibits T cell activation, differentiation, and proliferation, leading to a state of immune tolerance. Blocking these interactions recently emerged as a 'game changer' approach in immunotherapy. Despite the significant therapeutic potential of targeting the PD-1 pathway, the interaction between human PD-1 and its two human ligands is not fully understood. Current crystal structures describe the interactions of mouse PD-1 with human PD-L1 or mouse PD-L2. However, recent mutational and nuclear magnetic resonance (NMR) analyses suggest that human PD-1 binds its human ligands differently compared to their mouse counterparts. No detailed model is currently available to consistently fit these data. The lack of these accurate structures constitutes a high barrier against rationally developing more effective and safer agents targeting these interactions. Here we describe for the first time two accurate models for human PD-1 bound to its two human ligands. Our methodology involved combining molecular dynamics (MD) simulations with protein-protein docking and binding energy analysis to predict the most probable binding conformations for PD1 to its ligands. Our results confirm the available experimental NMR and mutational data and reveal the most accurate atomistic details so far of how human PD-1 binds to human PD-Ls and why the two ligands bind with different affinities to the same receptor.


Assuntos
Antígeno B7-H1/metabolismo , Modelos Moleculares , Sequência de Aminoácidos , Animais , Apoproteínas/química , Antígeno B7-H1/química , Humanos , Ligantes , Camundongos , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Ligação Proteica , Conformação Proteica , Alinhamento de Sequência , Homologia Estrutural de Proteína , Termodinâmica
15.
Drug Discov Today ; 20(5): 548-61, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25622780

RESUMO

Chronic infection with hepatitis B virus (HBV) often leads to the development of liver cancer and cirrhosis, creating immense sociological, clinical and economic burdens worldwide. Although current anti-HBV medications manage to control the disease progression and help restore normal liver functions, they often fail to eliminate the virus completely. A major reason for this failure is the presence of a stable viral genome in the hepatocyte nucleus: the covalently closed circular DNA (cccDNA). Targeting HBV cccDNA is a promising approach that could lead to a complete cure. Here, we review various research approaches that are directed toward eliminating HBV cccDNA. This is a brief, yet comprehensive, summary of current state-of-the-art developments in this emerging area of interest.


Assuntos
Antivirais/uso terapêutico , DNA Circular/efeitos dos fármacos , DNA Viral/efeitos dos fármacos , Desenho de Drogas , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Animais , DNA Circular/genética , DNA Viral/genética , Genótipo , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/virologia , Humanos , Estrutura Molecular , Terapia de Alvo Molecular , Indução de Remissão , Relação Estrutura-Atividade , Resultado do Tratamento , Carga Viral
16.
J Phys Chem A ; 118(20): 3645-54, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24821292

RESUMO

The electronic structures and properties of 2-oxazolidinone and the related compound cycloserine (CS) have been investigated using theoretical calculations and core and valence photoelectron spectroscopy. Isomerization of the central oxazolidine heterocycle and the addition of an amino group yield cycloserine. Theory correctly predicts the C, N, and O 1s core spectra, and additionally, we report theoretical natural bond orbital (NBO) charges. The valence ionization energies are also in agreement with theory and previous measurements. Although the lowest binding energy part of the spectra of the two compounds shows superficial similarities, further analysis of the charge densities of the frontier orbitals indicates substantial reorganization of the wave functions as a result of isomerization. The highest occupied molecular orbital (HOMO) of CS shows leading carbonyl π character with contributions from other heavy (non-H) atoms in the molecule, while the HOMO of 2-oxazolidinone (OX2) has leading nitrogen, carbon, and oxygen pπ characters. The present study further theoretically predicts bond resonance effects of the compounds, evidence for which is provided by our experimental measurements and published crystallographic data.


Assuntos
Ciclosserina/química , Oxazolidinonas/química , Teoria Quântica , Estrutura Molecular , Espectroscopia Fotoeletrônica
17.
J Enzyme Inhib Med Chem ; 29(2): 215-22, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23402383

RESUMO

Herein, we designed and synthesized certain anilinoquinazoline derivatives bearing bulky arylpyridinyl, arylpropenoyl and arylpyrazolyl moieties at the 4' position of the anilinoquinazoline, as potential dual HER2/EGFR kinase inhibitors. A detailed molecular modeling study was performed by docking the synthesized compounds in the active site of the epidermal growth factor receptor (EGFR). The synthesized compounds were further tested for their inhibitory activity on EGFR and HER2 tyrosine kinases. The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR with IC50 equal to 2.09 and 1.94 µM, respectively, and with IC50 equal to 3.98 and 1.04 µM on HER2, respectively. Furthermore, the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines, known to overexpress EGFR, showed an IC50 range of 2.4 and 2.5 µM, respectively.


Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia
18.
J Mol Graph Model ; 44: 220-31, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23911931

RESUMO

Based on the hit structures that have been identified in our previous studies against EGFR and HER2, new potential inhibitors that share the same scaffold of the hit structures are designed and screened in silico. Insights into understanding the potential inhibitory effect of the new inhibitors against both EGFR and HER2 receptors is obtained using extended molecular dynamics (MD) simulations and different scoring techniques. The binding mechanisms and dynamics are detailed with respect to two approved inhibitors against EGFR (lapatinib) and HER2 (SYR127063). The best scoring inhibitor (T9) is chosen for additional in silico investigation against both the wild-type and T790M mutant strain of EGFR and the wild-type HER2. The results reveal that certain substitution patterns increase the stability and assure stronger binding and higher H-bond occupancy of the conserved water molecule that is commonly observed with kinase crystal structures. Furthermore, the new inhibitor (T9) forms stable interactions with the mutant strain as a direct consequence of the enhanced ability to form additional hydrogen bonding interactions with binding site residues.


Assuntos
Simulação por Computador , Receptores ErbB/química , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Receptor ErbB-2/química , Sítios de Ligação , Desenho de Drogas , Receptores ErbB/antagonistas & inibidores , Humanos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptor ErbB-2/antagonistas & inibidores , Água/química
19.
J Mol Graph Model ; 40: 91-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23353584

RESUMO

In the development of new anti-cancer drugs to tackle the problem of resistance to current chemotherapeutic agents, a new series of anti-HER2 (human epidermal growth factor receptors 2) agents has been synthesized and investigated using different computational methods. Although non-selective, the most active inhibitor in the new series shows higher activity toward HER2 than EGFR. The induced fit docking protocol (IFD) is performed to find possible binding poses of the new inhibitors in the active site of the HER2 receptor. Molecular dynamic simulations of the inhibitor-protein complexes for the two most active compounds from the new series are carried out. Simulations stability is checked using different stability parameters. Different scoring functions are employed.


Assuntos
Desenho de Drogas , Ligantes , Modelos Moleculares , Receptor ErbB-2/química , Relação Estrutura-Atividade , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Ligação Proteica , Teoria Quântica , Receptor ErbB-2/antagonistas & inibidores
20.
J Phys Chem A ; 116(33): 8653-60, 2012 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-22799571

RESUMO

X-ray photoelectron spectra of the core and valence levels of the fundamental building blocks of ß-lactam antibiotics have been investigated and compared with theoretical calculations. The spectra of the compounds 2-azetidinone and the 2- and 4-isomers of thiazolidine-carboxylic acid are interpreted in the light of theoretical calculations. The spectra of the two isomers of thiazolidine-carboxylic acid are rather similar, as expected, but show clear effects due to isomerization. Both isomers are analogues of proline, which is well-known to populate several low energy conformers in the gas phase. We have investigated the low energy conformers of thiazolidine-4-carboxylic acid theoretically in more detail and find some spectroscopic evidence that multiple conformers may be present. The measured valence levels are assigned for all three compounds, and the character of the frontier orbitals is identified and analyzed.


Assuntos
Antibacterianos/química , Azetidinas/química , Espectroscopia Fotoeletrônica , Prolina/análogos & derivados , Tiazolidinas/química , Prolina/química , Teoria Quântica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA