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1.
Therapie ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34689960

RESUMO

SARS-CoV-2 is a positive-sense RNA virus and it is the causative agent of the global COVID-19 outbreak. COVID-19 is similar to the previous outbreaks for instance SARS in 2002-2003 and MERS in 2012. As the peptides have many advantages, peptide-based therapeutics might be one of the possible ways in the development of COVID-19 specific drugs. SARS-CoV-2 enters into a human via its S protein by attaching with human hACE2 present on the cell membrane in the lungs and intestines of humans. hACE2 cleaves S protein into the S1 subunit for viral attachment and the S2 subunit for fusion with the host cell membrane. The fusion mechanism forms a six-helical bundle (6-HB) structure which finally fuses the viral envelope with the host cell membrane. hACE2 based peptides such as SBP1 and Spikeplug have shown their potential as antiviral agents. S protein-hACE2 interaction and the SARS-CoV-2 fusion machinery play a crucial part in human viral infection. It is evident that if these interactions could be blocked successfully and efficiently, it could be the way to find the drug for COVID-19. Several peptide-based inhibitors are potent inhibitors of S protein-hACE2 interaction. Similarly, the antiviral activity of the antimicrobial peptide, lactoferrin makes it an important candidate for the COVID-19 drug development process. A candidate drug, RhACE2-APN01 based on recombinant hACE2 peptide has already entered phase II clinical trials. This review sheds light on different aspects of the feasibility of using peptide-based therapeutics as the promising therapeutic route for COVID-19.

2.
Curr Drug Targets ; 22(14): 1688-1703, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33618645

RESUMO

The neuron is high-energy utilizing tissue. The rate of neuronal cell respiration is higher than in other cells. Cellular respiration occurs with mitochondria. The healthy production and functions of mitochondria play a key role in the maintenance of healthy neurons. In pathological conditions such as neurodegenerative diseases, healthy mitochondria help to alleviate pathological events in neuronal cells. Conversely, mitochondrial dysfunction promotes the acceleration of the neurodegenerative process. Furthermore, glial-derived mitochondria contribute to multiple roles in the regulation of healthy neuron functions. It also supports releasing of the neurotransmitters; generation of the impulses, regulation of the membrane potential and molecular dynamics; controlling of the axonal transport; controlling of the mitochondrial fission and fusion functions in the peripheral as well as the central nervous system. Moreover, it plays a key role in the regeneration process of neuronal cells. Therefore, healthy mitochondria can provide a healthy environment for neuronal cell function and can treat neurodegenerative disorders. In this review, we explore the current view of healthy mitochondria and their role in healthy neuronal functions.


Assuntos
Mitocôndrias/fisiologia , Doenças Neurodegenerativas , Neurônios/fisiologia , Humanos , Dinâmica Mitocondrial , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo
3.
ACS Omega ; 6(1): 265-277, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33458478

RESUMO

In this study, novel self-assembled carbazole-thiooctanoic acid nanoparticles (CTNs) were synthesized from amino carbazole (a mutagen) and thiooctanoic acid (an antioxidant). The nanoparticles were characterized using hyperspectral techniques. Then, the antiproliferative potential of CTNs was determined in HepG2 liver carcinoma cells. This study employed a solvent-antisolvent interaction method to synthesize a spherical CTN of size less than 50 nm. Moreover, CT was subsequently capped to gold nanoparticles (AuNPs) in the additional comparative studies. The CT derivative was synthesized from carbazole and lipoic acid by the amide bond formation reaction using a coupling agent. Furthermore, it was characterized using infrared (IR), 1H nuclear magnetic resonance, dynamic light scattering (DLS), and transmission electron microscopy techniques. The CT-capped gold nanoparticles (CTAuNPs) were prepared from CT, chloroauric acid, and NaBH4. The CTAuNPs were characterized using ultraviolet-visible, high-resolution TEM, DLS, and Fourier transform IR techniques. The cytotoxicity and apoptosis-inducing ability of both nanoparticles were determined in HepG2 cells. The results demonstrate that CTNs exhibit antiproliferative activity in the cancerous HepG2 cells. Moreover, molecular docking and molecular dynamics studies were conducted to explore the therapeutic potential of CT against human EGFR suppressor protein to gain more insights into the binding mode of the CT, which may show a significant role in anticancer therapy.

4.
Comb Chem High Throughput Screen ; 23(9): 887-897, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208114

RESUMO

Monoamine oxidases are the crucial drug targets for the treatment of neurodegenerative disorders like depression, Parkinson's disease, and Alzheimer's disease. The enzymes catalyze the oxidative deamination of several monoamine containing neurotransmitters, i.e. serotonin (5-HT), melatonin, epinephrine, norepinephrine, phenylethylamine, benzylamine, dopamine, tyramine, etc. The oxidative reaction of monoamine oxidases results in the production of hydrogen peroxide that leads to the neurodegeneration process. Therefore, the inhibition of monoamine oxidases has shown a profound effect against neurodegenerative diseases. At present, the design and development of newer lead molecules for the inhibition of monoamine oxidases are under intensive research in the field of medicinal chemistry. Recently, the advancement in QSAR methodologies has shown considerable interest in the development of monoamine oxidase inhibitors. The present review describes the development of QSAR methodologies, and their role in the design of newer monoamine oxidase inhibitors. It will assist the medicinal chemist in the identification of selective and potent monoamine oxidase inhibitors from various chemical scaffolds.


Assuntos
Inibidores da Monoaminoxidase/química , Monoaminoxidase/química , Doença de Alzheimer/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Desenho de Fármacos , Feminino , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Masculino , Inibidores da Monoaminoxidase/farmacologia , Mutação , Oxirredução , Doença de Parkinson/tratamento farmacológico , Relação Quantitativa Estrutura-Atividade , Relação Estrutura-Atividade
5.
Drug Metab Lett ; 13(1): 64-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30210009

RESUMO

BACKGROUND: Diclofenac is a non-steroidal antiinflammatory drug. It is predominantly metabolized by CYP2C9. 4'-hydroxydiclofenac and its quinoneimine are the metabolites of diclofenac. However, few numbers of serious cases of idiosyncratic hepatotoxicity due to diclofenac metabolism were reported. The formation of the quinoneimine metabolite was found to be responsible for this idiosyncratic toxicity. Quinoneimine is an over-oxidized metabolite of diclofenac. METHOD: In this work, computational studies were conducted to detail the formation of a quinoneimine metabolite from diclofenac. Further, the idiosyncratic toxicity of quinoneimine due to its reactivity was also investigated by quantum chemical analysis. RESULTS & CONCLUSION: The results demonstrate the possibility of formation of quinoneimine metabolite due to various factors that are involved in the metabolism of diclofenac. The present study may provide the structural in-sights during the drug development processes to avoid the metabolism directed idiosyncratic toxicity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/análogos & derivados , Diclofenaco/farmacologia , Modelos Químicos , Química Farmacêutica , Simulação por Computador , Citocromo P-450 CYP2C9/metabolismo , Diclofenaco/química , Diclofenaco/toxicidade , Desenvolvimento de Medicamentos/métodos , Humanos , Microssomos Hepáticos , Oxirredução
6.
J Biomol Struct Dyn ; 36(14): 3687-3704, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29064326

RESUMO

Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSP is responsible for the establishment of the bipolar mitotic spindle which mediates cell division. Inhibition of KSP expedites the blockade of the normal cell cycle during mitosis through the generation of monoastral MT arrays that finally cause apoptotic cell death. As KSP is highly expressed in proliferating/cancer cells, it has gained considerable attention as a potential drug target for cancer chemotherapy. Therefore, this study envisaged to design novel KSP inhibitors by employing computational techniques/tools such as pharmacophore modelling, virtual database screening, molecular docking and molecular dynamics. Initially, the pharmacophore models were generated from the data-set of highly potent KSP inhibitors and the pharmacophore models were validated against in house test set ligands. The validated pharmacophore model was then taken for database screening (Maybridge and ChemBridge) to yield hits, which were further filtered for their drug-likeliness. The potential hits retrieved from virtual database screening were docked using CDOCKER to identify the ligand binding landscape. The top-ranked hits obtained from molecular docking were progressed to molecular dynamics (AMBER) simulations to deduce the ligand binding affinity. This study identified MB-41570 and CB-10358 as potential hits and evaluated these experimentally using in vitro KSP ATPase inhibition assays.


Assuntos
Antineoplásicos/química , Cinesina/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Antineoplásicos/farmacologia , Sítios de Ligação , Humanos , Cinesina/antagonistas & inibidores , Ligantes , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes
7.
Protein J ; 36(5): 385-396, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28762197

RESUMO

Aspartic proteases are a class of hydrolytic enzymes that have been implicated in a number of diseases such as HIV, malaria, cancer and Alzheimer's. The flap region of aspartic proteases is a characteristic unique structural feature of these enzymes; and found to have a profound impact on protein overall structure, function and dynamics. Flap dynamics also plays a crucial role in drug binding and drug resistance. Therefore, understanding the structure and dynamic behavior of this flap regions is crucial in the design of potent and selective inhibitors against aspartic proteases. Defining metrics that can describe the flap motion/dynamics has been a challenging topic in literature. This review is the first attempt to compile comprehensive information on sequence, structure, motion and metrics used to assess the dynamics of the flap region of different aspartic proteases in "one pot". We believe that this review would be of critical importance to the researchers from different scientific domains.


Assuntos
Ácido Aspártico Endopeptidases , Sequência de Aminoácidos , Ácido Aspártico Endopeptidases/análise , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Domínio Catalítico , Infecções por HIV , Protease de HIV , Humanos , Simulação de Dinâmica Molecular , Inibidores de Proteases , Renina
8.
Comb Chem High Throughput Screen ; 20(6): 492-509, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28294055

RESUMO

Background Due to the limited number of MAO inhibitors in the clinics, several research efforts are aimed at the discovery of novel MAO inhibitors. At present, a high specificity and a reversible mode of inhibition of MAO-A/B are cited as desirable traits in drug discovery process. This will help to reduce the probability of causing target disruption and may increase the duration of action of drug. AIM: Most of the existing MAO inhibitors lead to side effects due to the lack of affinity and selectivity. Therefore, there is an urgent need to design novel, potent, reversible and selective inhibitors for MAO-A/B. Selective inhibition of MAO-A results in the elevated level of serotonin and noradrenaline. Hence, MAO-A inhibitors can be used for improving the symptoms of depression. The selective MAO-B inhibitors are used with L-DOPA and/or dopamine agonists in the symptomatic treatment of Parkinson's disease. The present study was aimed to describe the recently developed hits of MAO inhibitors. METHOD: At present, CADD techniques are gaining an attention in rationale drug discovery of MAO inhibitors, and several research groups employed CADD approaches on various chemical scaffolds to identify novel MAO inhibitors. These computational techniques assisted in the development of lead molecules with improved pharmacodynamics / pharmacokinetic properties toward MAOs. Further, CADD techniques provided a better understanding of structural aspects of molecular targets and lead molecules. CONCLUSIONS: The present review describes the importance of structural features of potential chemical scaffolds as well as the role of computational approaches like ligand docking, molecular dynamics, QSAR and pharmacophore modeling in the development of novel MAO inhibitors.


Assuntos
Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Doença de Parkinson/tratamento farmacológico , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Doença de Parkinson/metabolismo , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 27(3): 370-386, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28017531

RESUMO

Modern chemotherapy has significantly improved patient outcomes against drug-sensitive tuberculosis. However, the rapid emergence of drug-resistant tuberculosis, together with the bacterium's ability to persist and remain latent present a major public health challenge. To overcome this problem, research into novel anti-tuberculosis targets and drug candidates is thus of paramount importance. This review article provides an overview of tuberculosis highlighting the recent advances and tools that are employed in the field of anti-tuberculosis drug discovery. The predominant focus is on anti-tuberculosis agents that are currently in the pipeline, i.e. clinical trials.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose/dietoterapia , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , DNA Bacteriano/química , DNA Bacteriano/metabolismo , Descoberta de Drogas , Farmacorresistência Bacteriana/efeitos dos fármacos , Genômica , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológico
10.
Cell Biochem Biophys ; 75(1): 49-64, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27981421

RESUMO

Human immunodeficiency virus (HIV)-negative factor (Nef) protein is an accessory pathogenic factor, which plays a significant role in acquired immune deficiency syndrome (AIDS). Nef deficient HIV virus took a longer time to progress into AIDS. Therefore, targeting Nef protein is considered as a key strategy towards HIV/AIDS treatment. Up-to-date, only few compounds were reported as Nef inhibitors. This has prompted us to provide a first account of an integrated computational framework in order to identify more potential Nef inhibitors. Herein, using a hybrid ligand (shape similarity and pharmacophore) and structure-(molecular docking) based virtual screening approaches combined with molecular dynamics as well as post dynamics analysis, potential new hits were identified as HIV-Nef inhibitors. The top ranked compounds of molecular docking from the shape similarity-based library (ZINC04177596, ∆ G bind= -28.7482 kcal/mol) and pharmacophore-based library (ZINC36617540, ∆ G bind= -20.2271 kcal/mol) possess comparatively better binding affinities than the reference molecule, B9 (∆ G bind = -18.0694 kcal/mol). Both these hits (ZINC04177596 and ZINC36617540) showed similar binding mode at the binding site as like the prototype, B9. Hydrophobic and electrostatic interactions seemed to be the prominent binding forces that hold these ligands at the dimer interface of Nef protein. Finally, a set of chemical structural features that can be used as a guide in the design of novel potential Nef inhibitors is also highlighted herein. We believe that the information gained from this study would be of great importance in the discovery and design of potential small molecules targeting HIV-Nef.


Assuntos
Fármacos Anti-HIV/química , Produtos do Gene nef do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios Proteicos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Termodinâmica , Produtos do Gene nef do Vírus da Imunodeficiência Humana/química
11.
Neurosci Lett ; 628: 10-6, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27288016

RESUMO

Clinically, ischemic environment during gynecological surgery at lithotomy position is most common causative factor for the development of vasculitic femoral neuropathy (VFN). The present study was designed to induce the clinically relevant rat model of VFN by ischemic-reperfusion (I/R) injury of unilateral external iliac artery (uEIA). The VFN was induced by 3, 4 and 5h occlusion of uEIA followed by reperfusion. The I/R of uEIA induced VFN was evaluated by (i) behavioral parameters i.e., hind limb temperature; weight bearing capacity; (ii) kinematic analysis i.e., paw posture, splay angle, static sciatic index (SSI), and ankle-angle tests; (iii) evaluation of pain perception i.e., plantar and pin prick; (iv) serum biochemical estimation i.e., nitrate, lipid peroxidation, TNF-α and calcium level; (v) evaluation of motor and sensory nerve conduction velocity; and (vi) measurement of nerve fiber density. The 4 and 5h occlusion of uEIA has produced the potential changes in behavioral, functional, electrophysiological, biochemical and histopathological assessment. The 5h occlusion of uEIA has shown to produce the mortality. Whereas, 3h occlusion does not produce the significant changes in the development of VFN. The 4h ischemic occlusion of uEIA has shown potential rat model of VFN due to its close mimicking capacity of VFN in human. Therefore, it can be useful to explore the newer anti-neuralgic medicine and with their pharmacodynamic action in the field of various neurovascular disorders.


Assuntos
Modelos Animais de Doenças , Neuropatia Femoral , Artéria Ilíaca/lesões , Neuralgia , Animais , Fenômenos Biomecânicos , Neuropatia Femoral/etiologia , Neuropatia Femoral/fisiopatologia , Neuropatia Femoral/psicologia , Masculino , Condução Nervosa , Neuralgia/etiologia , Neuralgia/fisiopatologia , Neuralgia/psicologia , Estresse Oxidativo , Percepção da Dor , Limiar da Dor , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/psicologia
12.
Drug Des Devel Ther ; 10: 1365-77, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27114700

RESUMO

A novel virtual screening approach is implemented herein, which is a further improvement of our previously published "target-bound pharmacophore modeling approach". The generated pharmacophore library is based only on highly contributing amino acid residues, instead of arbitrary pharmacophores, which are most commonly used in the conventional approaches in literature. Highly contributing amino acid residues were distinguished based on free binding energy contributions obtained from calculation from molecular dynamic (MD) simulations. To the best of our knowledge; this is the first attempt in the literature using such an approach; previous approaches have relied on the docking score to generate energy-based pharmacophore models. However, docking scores are reportedly unreliable. Thus, we present a model for a per-residue energy decomposition, constructed from MD simulation ensembles generating a more trustworthy pharmacophore model, which can be applied in drug discovery workflow. This work is aimed at introducing a more rational approach to the field of drug design, rather than comparing the validity of this approach against those previously reported. We recommend additional computational and experimental work to further validate this approach. This approach was used to screen for potential reverse transcriptase inhibitors using the pharmacophoric features of compound GSK952. The complex was subjected to docking, thereafter, MD simulation confirmed the stability of the system. Experimentally determined inhibitors with known HIV-reverse transcriptase inhibitory activity were used to validate the protocol. Two potential hits (ZINC46849657 and ZINC54359621) showed a significant potential with regard to free binding energy. Reported results obtained from this work confirm that this new approach is favorable in the future of the drug design industry.


Assuntos
Fármacos Anti-HIV/análise , Fármacos Anti-HIV/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , HIV/enzimologia , Inibidores da Transcriptase Reversa/análise , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/metabolismo , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/química
13.
J Inorg Biochem ; 157: 15-24, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26824520

RESUMO

Computational studies were conducted to identify the favourable formation of the inclusion complex of chloramphenicol with cyclodextrins. The results of molecular docking and molecular dynamics predicted the strongest interaction of chloramphenicol with γ-cyclodextrin. Further, the inclusion complex of chloramphenicol with γ-cyclodextrin was experimentally prepared and a phenomenon of inclusion was verified by using different characterization techniques such as thermogravimetric analysis, differential scanning calorimetry, (1)H nuclear magnetic resonance (NMR) and two dimensional nuclear overhauser effect spectroscopy (NOESY) experiments. From these results it was concluded that γ-cyclodextrins could be an appropriate cyclodextrin polymer which can be used to functionalize chloramphenicol on the surface of silver nanoparticles. In addition, γ-cyclodextrin capped silver nanoparticles were synthesized and characterized using UV-visible spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray analysis (EDX), Fourier transform infrared spectroscopy (FTIR) and zeta potential analysis. Molecular recognition of chloramphenicol by these cyclodextrin capped silver nanoparticles was confirmed by surface enhanced raman spectroscopy (SERS) experiments. Synergistic antibacterial effect of chloramphenicol with γ-cyclodextrin capped silver nanoparticles was evaluated against Pseudomonas aeruginosa (ATCC 27853), Enterococcus faecalis (ATCC 5129), Klebsiella pneumoniae (ATCC 700603) and Staphylococcus aureus (ATCC 43300). The results from the antibacterial experiment were favourable thus allowing us to conclude that the approach of modifying organic drug molecules with cyclodextrin capped inorganic silver nanoparticles could help to enhance the antibacterial activity of them.


Assuntos
Antibacterianos/farmacologia , Cloranfenicol/farmacologia , Nanopartículas Metálicas , Prata/química , gama-Ciclodextrinas/química , Microscopia Eletrônica de Varredura , Simulação de Dinâmica Molecular , Análise Espectral
14.
Appl Biochem Biotechnol ; 178(8): 1546-66, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26743758

RESUMO

We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains.


Assuntos
Dendrímeros/farmacologia , Glucosamina/análogos & derivados , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Proteínas de Ligação às Penicilinas/química , Antibacterianos/química , Antibacterianos/farmacologia , Dendrímeros/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Glucosamina/química , Glucosamina/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
15.
J Phys Chem B ; 118(31): 9199-208, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25014395

RESUMO

The self-association behavior of a newly characterized ß-strand-mimic, presented by an achiral nonproteinogenic model system Boc-γ-Abz-NHMe (1: Boc = tert-butyloxycarbonyl; γ-Abz = γ-aminobenzoic acid; NHMe = N-methylamide), have been investigated using (1)H NMR and FT-IR absorption spectroscopy, in combination with computational ab initio calculations. The concentration dependence of (1)H NMR chemical shifts of the amide-NHs in CDCl3 exhibited noncooperative behavior of self-association, whereas the variable temperature (1)H NMR chemical shifts data of the amide-NHs, i.e., temperature-coefficient (Δδ/ΔT) values, could be accounted for by significant enhancement of self-association, i.e., aggregates higher than dimers. In the absence of N-H···O intramolecular H-bond in 1, the intense FT-IR absorption bands in informative amide-A region, i.e., N-H stretches at ∼3465 and 3438 cm(-1) in chloroform solution, could be interpreted in terms of intermolecular H-bonding. The ab initio quantum mechanical calculations performed on two discrete isolated antiparallel H-bonded duplexes with a face-to-face and an edge-to-edge aromatic-aromatic interaction provided strong support for their relative importance to stabilize favorable dimeric structures. The thermodynamic parameters deduced from van't Hoff plots, constructed from variable temperature (1)H NMR data of the amide-NHs in CDCl3, also substantiated the effectiveness of aromatic-aromatic interactions for dimer formation and higher-order self-association. In view of the enormous structural importance of ß-strand-like building blocks in peptide design, we highlight intrinsic self-associating potentials of the readily available γ-Abz moiety, besides the fact that such planar secondary structural mimics are presumed to offer greater prospective for constructing peptidomimetics and therapeutically relevant small molecules.


Assuntos
Aminobenzoatos/química , Ésteres do Ácido Fórmico/química , Peptídeos/química , Estrutura Secundária de Proteína , Solventes/química , Algoritmos , Clorofórmio/química , Simulação por Computador , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Termodinâmica
16.
Curr Drug Targets ; 15(2): 210-53, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24093749

RESUMO

Understanding mechanism of neuropathic pain is too complex and involves both peripheral and central pathophysiological phenomenon. Accordingly the treatment of neuropathic pain is also very complex and is unsatisfactory. The present review attempts to discuss the currently employed pharmacological agents for the management of neuropathic pain including anti-depressants, anti-convulsants, NMDA receptor antagonists, topical & local anesthetics, and upload analgesics. However, the existing pharmacotherapy has marginal efficacy and significant side effects. The review also gives an insight into various pharmacological agents with potential neuropathic pain attenuating properties in experimental models that include NSAIDs, corticosteroids, ion channel blockers (Ca(2+), Na(+), K(+), and TRP channel); ion exchange modulators (NCE and NHE); ion/molecule transport modulators (NKCC-1 and glycine); receptor modulators (kinin, histamine, 5-HT1A, dopamine, alpha & beta adrenergic, purinergic, excitatory amino acid, sigma, ORL1, endothelin, melanocortin, ephrin and PAR); enzyme inhibitors (cytosolic kinase, metalloproteinase, protease, vasopeptidase, D-amino acid oxidase, fatty acid amide hydrolase, aldose reductase and sorbitol dehydrogenase); other ligands (AGE, RAGEs, neuropeptides, neurotrophic factor, complement cascade, cytokine, glial cell & gap junction, nitrous oxide, growth factor, cell adhesion molecule and neuronal sprouting molecule). Moreover, some advanced therapeutic approaches such as neuronal cell transplantation, stem cell therapy, anti-sense oligonucleotide and recombinant therapy have also been dicussed.


Assuntos
Analgésicos/uso terapêutico , Antidepressivos/uso terapêutico , Descoberta de Drogas , Terapia de Alvo Molecular , Neuralgia/tratamento farmacológico , Analgésicos/química , Analgésicos/farmacologia , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Transplante de Células , Humanos , Neuralgia/patologia , Neuralgia/terapia
17.
Naunyn Schmiedebergs Arch Pharmacol ; 385(7): 739-48, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22526471

RESUMO

This study was designed to investigate the role of 7,8-dimethoxycoumarin on cisplatin- and ischemia/reperfusion (I/R)-induced acute renal failure in rats. Acute renal failure was induced in rats by administration of a single dose of cisplatin (CP) (6 mg/kg, intraperitoneally on day 6) and occlusion of the left renal artery for 45 min (I) and opened for the next 24 h (R). The drug samples of 7,8-dimethoxycoumarin (DMC, 50, 75, and 100 mg/kg) and cyclosporin A (50 µM/kg) were administered orally for six consecutive days. Administration of a single dose of cisplatin and I/R event has significantly raised blood urea nitrogen and creatinine, N-acetyl beta-D: -glucosaminidase, and thiobarbituric acid reactive substances but decreased FrNa, creatinine clearance, reduced glutathione (GSH), mitochondrial cytochrome c oxidase, and adenosine triphosphate levels. Further, pretreatment of DMC (50, 75, and 100 mg/kg, p.o., for six consecutive days) has ameliorated the CP- and I/R-induced biochemical and histopathological changes in a dose-dependent manner. Furthermore, 75 and 100 mg/kg of 7,8-dimethoxycoumarin has shown to possess the significant renoprotective effect similar to that of the cyclosporin A-treated group which served as positive control. Based on the results of the present study, it has been concluded that 7,8-dimethoxycoumarin protects the kidney against the CP and I/R injury via antioxidant, anti-inflammatory, and inactivation of mitochondrial permeability transition pore opening.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Cumarínicos/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Trifosfato de Adenosina/metabolismo , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Cisplatino , Citrus , Cumarínicos/isolamento & purificação , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
18.
Life Sci ; 90(19-20): 755-62, 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22483690

RESUMO

AIMS: Ischemia-reperfusion (I/R) event in vascular and nervous system has been documented to rising ischemic and vasculitic neuropathic pain, clinically resembles the complex regional pain syndrome (CRPS). The present study evaluated the effect of montelukast, a cysteinyl leukotriene receptor (Cys-LTC(4) and Cys-LTD(4)) antagonist on ischemia -reperfusion (I/R) induced vasculitic neuropathic pain in rats. MAIN METHODS: Behavioral parameters were assessed at different time intervals (i.e. 0, 1, 7, 14 and 21st day) and biochemical analysis in sciatic nerve tissue samples were also performed along with histopathological studies. KEY FINDINGS: Behavioral pain assessment has shown increase in paw and tail withdrawal threshold in montelukast treated groups against thermal and mechanical stimuli as compared to I/R control group. We observed a decrease in the total calcium, thiobarbituric acid reactive substance (TBARS) and myeloperoxidase (MPO) activity levels, whereas there is rise in reduced glutathione level in montelukast treated groups as compared to I/R control group. However, significant behavioral and biochemical results were observed only in medium and high dose of treated groups which were comparable to normal control group. Moreover, histopathological study has revealed the reduction of I/R induced neuronal edema and axonal degeneration due to montelukast. SIGNIFICANCE: Montelukast has ameliorated I/R induced vasculitic neuropathic pain, these effects may be due to inhibition of lipid peroxidation, reduction of oxidative stress, release of inflammatory mediators and neuroprotective actions. Hence, it could be used as a novel therapeutic agent for the management of vasculitic inflammation related neuropathic pain.


Assuntos
Acetatos/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Neuralgia/complicações , Quinolinas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Vasculite/complicações , Acetatos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Cálcio/metabolismo , Glutationa/metabolismo , Temperatura Alta , Imersão , Antagonistas de Leucotrienos/administração & dosagem , Neuralgia/patologia , Neuralgia/psicologia , Medição da Dor , Peroxidase/metabolismo , Estimulação Física , Quinolinas/administração & dosagem , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Traumatismo por Reperfusão/psicologia , Nervo Isquiático/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Vasculite/patologia , Vasculite/psicologia
19.
Dig Dis Sci ; 56(8): 2244-51, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21327706

RESUMO

OBJECTIVES: Ischemia-reperfusion is a major event for induction of cellular apoptosis. Apoptosis is due to the activation of death receptor and/or mitochondrial pathways. Mitochondrial permeability transition pore opening is the cause of apoptosis. In our present study, we tried to evaluate the role of flunarizine in ischemia and reperfusion of celiac artery-induced gastric lesion in the rat. METHODS: The therapeutic potential of flunarizine was assessed by measuring the changes in gastric lesion index, biomarker (i.e., thiobarbituric acid reactive substance, reduced glutathione, superoxide dismutase, myeloperoxidase, and total calcium and protein content), and mitochondrial damage (i.e., adenosine triphosphate and deoxyribonucleic acid fragmentation content) in ischemia and reperfusion-induced gastric lesion model. RESULTS: Medium and higher doses of flunarizine produced a significant (P<0.05) ameliorative effect which was observed from the assessment of all the above-mentioned parameters (i.e., increase in reduced glutathione, superoxide dismutase and decrease in thiobarbituric acid reactive substance, myeloperoxidase, and total calcium content). Similar results were also obtained from omeprazole and cyclosporine. In the pre-treated group, deoxyribonucleic acid fragmentation pattern has also indicated that a mitochondria-associated anti-apoptotic effect of flunarizine was responsible to prevent the ischemia and reperfusion of celiac artery-induced gastric lesion. CONCLUSION: The gastroprotective effect of flunarizine may be produced due to its inactivation potential of mitochondrial permeability transition pore opening associated with anti-oxidative, calcium regulation along with its anti-apoptotic effect.


Assuntos
Apoptose/efeitos dos fármacos , Flunarizina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Estômago/irrigação sanguínea , Vasodilatadores/uso terapêutico , Animais , Antiulcerosos/uso terapêutico , Cálcio/metabolismo , Artéria Celíaca/fisiopatologia , Ciclosporina/uso terapêutico , Glutationa/metabolismo , Imunossupressores/uso terapêutico , Masculino , Omeprazol/uso terapêutico , Peroxidase/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Estômago/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
20.
J Neurosci Methods ; 186(2): 215-21, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20026113

RESUMO

Ischemic-reperfusion (I/R) is common in various pathological conditions like diabetic complication, complex regional pain syndrome type II (CRPS II), necrotizing vascular occlusive disease and trauma. We have developed an animal model of ischemic-reperfusion injury induced nociceptive sensory neuropathy in rats. The model was validated after 2, 4 and 6h of ischemia followed by prolonged reperfusion. The sensory behavioral assessment revealed thermal and mechanical hyperalgesia in paw and in tail which expressed the peripheral and central neuropathic pain respectively. We observed a decrease in the serum IL-10 and nerve conduction velocity and increase in the serum nitrate, malondialdehyde (MDA) and TNF-alpha levels in the 4 and 6h I/R groups in biochemical and electrophysiological evaluations. Histopathological study had revealed the decrease in nerve fiber density in the moderate and severe I/R groups. We selected the moderate (4h) ischemic-reperfusion injury as beneficial model because of the good correlation with clinical status for the development of neuropathy in human associated with severe pain disorders. This model can be used to explore pathophysiological mechanisms implied in the genesis of neuropathic pain and also to evaluate the new analgesic agents, peripheral neuro-vasoactive substances and neuroprotective drugs.


Assuntos
Modelos Animais de Doenças , Doenças do Sistema Nervoso Periférico , Ratos , Transtornos das Sensações , Animais , Artéria Femoral , , Temperatura Alta , Interleucina-10/sangue , Malondialdeído/sangue , Condução Nervosa , Nitratos/sangue , Medição da Dor , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Estimulação Física , Ratos Wistar , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transtornos das Sensações/etiologia , Transtornos das Sensações/patologia , Transtornos das Sensações/fisiopatologia , Cauda , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue
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