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1.
RSC Adv ; 12(17): 10336-10344, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35425015

RESUMO

The conformational and structural stability of n-propanethiol (nP) is revisited owing to the prevailing ambiguity in the literature reported hitherto, and the rationale for 2-propanethiol's (2P) most stable conformers is analyzed. Based on the rotation around the C-C and C-S bonds, four conformers for nP and two conformers for 2-propanethiol (2P) were found to have the lowest energies at the CCSD/cc-pVDZ level of theory. The two conformers of 2P are anti (T), and gauche (G), and those of nP are T-G, G-G, T-T, and G-T. Rotational barriers, geometrical parameters, fundamental vibrational modes, and energy parameters reported herein agree exceedingly well with the reported experimental values for nP and 2P molecules. Furthermore, natural bond orbital (NBO), frontier molecular orbital (FMO), Mulliken charge (MC), electrostatic potential charge (ESP), and vibrational mode analyses were carried out to get a better understanding of both the thiols.

2.
Life (Basel) ; 12(3)2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35330134

RESUMO

Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.

3.
Dev Comp Immunol ; 132: 104403, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35339533

RESUMO

Photoperiod and melatonin are important regulators of immunity. We hypothesized that these two factors play an important role in the regulation of immune responses in the Natrix piscator. Animals were kept in either short or long days and splenocyte immune responses were studied. Respiratory burst activity of splenocytes was assessed through reduction of nitrobluetetrazolium salt while production of nitric oxide was assessed indirectly by nitrite assay. Density gradient centrifugation was used to isolate splenic lymphocytes which were utilized to study proliferation with and without mitogens. Super oxide production by splenocytes was reduced significantly in the cultures obtained from animals kept either in short or long days. Nitrite release was decreased when animals were subjected to long days. The photoperiodic alterations acted differentially on proliferations of the splenic lymphocytes. Spontaneous and mitogen-induced proliferation of splenic lymphocytes were enhanced in cultures obtained from snakes maintained in short days when compared with cultures from snakes obtained either from long day or natural day length conditions. In vitro melatonin significantly enhanced the splenic lymphocyte proliferation of the cultures obtained from animals kept in long days when compared with splenic lymphocyte proliferations of the cultures obtained from long day animals or the animals kept in natural day length conditions. We found evidence which suggest that photoperiod may influence seasonal energy budgets and induce adjustments which optimize energy allocation for costly physiological processes such as immune function. In seasonally breeding animals such as Natrix piscator, the pineal hormone melatonin assists in the suppression of reproduction and elevation of immunity, which are the crucial adaptation for perpetuation of species.

4.
Transl Psychiatry ; 12(1): 127, 2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35351881

RESUMO

Epidemiological studies have proven that exposure to Arsenic (AS) leads to the development of many neurological disorders. However, few studies have investigated its molecular mechanisms in the brain. Our previous work has revealed nitric oxide (NO)-mediated apoptosis and SNO reprogramming in the cortex following arsenic treatment, yet the role of NO and S-nitrosylation (SNO) in AS-mediated neurotoxicity has not been investigated. Therefore, we have conducted a multidisciplinary in-vivo study in mice with two different doses of Sodium Arsenite (SA) (0.1 ppm and 1 ppm) in drinking water. We used the novel SNOTRAP-based mass spectrometry method followed by the bioinformatics analysis, Western blot validation, and five different behavioral tests. Bioinformatics analysis of SA-treated mice showed significant SNO-enrichment of processes involved in mitochondrial respiratory function, endogenous antioxidant systems, transcriptional regulation, cytoskeleton maintenance, and regulation of apoptosis. Western blotting showed increased levels of cleaved PARP-1 and cleaved caspase-3 in SA-treated mice consistent with SA-induced apoptosis. Behavioral studies showed significant cognitive dysfunctions similar to those of Autism spectrum disorder (ASD) and Alzheimer's disease (AD). A comparative analysis of the SNO-proteome of SA-treated mice with two transgenic mouse strains, models of ASD and AD, showed molecular convergence of SA environmental neurotoxicity and the genetic mutations causing ASD and AD. This is the first study to show the effects of AS on SNO-signaling in the striatum and hippocampus and its effects on behavioral characteristics. Finally, further investigation of the NO-dependent mechanisms of AS-mediated neurotoxicity may reveal new drug targets for its prevention.


Assuntos
Doença de Alzheimer , Arsênio , Transtorno do Espectro Autista , Doença de Alzheimer/genética , Animais , Arsênio/toxicidade , Transtorno do Espectro Autista/genética , Camundongos , Mutação , Óxido Nítrico
5.
J Biomol Struct Dyn ; : 1-15, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35014594

RESUMO

Leishmania donavani is the causative agent of leishmaniasis, responsible for social and economic disruption, especially in developing countries. Lack of effective drugs with few side effects have necessitated the discovery of newer therapeutic solutions for leishmaniasis. Glycophosphatidylinositol (GPI) synthesis plays a vital role in protozoan cell membranes structural formation and antigenic modification. Hence, any disruption in its biosynthesis can prove fatal to the parasitic protozoans. N-acetylglucosamine-phosphatidylinositol de-N-acetylase (NAGP-deacetylase) is an enzyme from the GPI biosynthetic pathway that catalyzes the deacetylation of N-acetylglucosaminylphosphatidylinositol to glucosaminylphosphatidylinositol, a step essential for the proper functioning of the enzyme. In the quest for novel scaffolds as anti-leishmaniasis agents, we have executed in silico virtual screening, density function theory, molecular dynamics and MM-GBSA based energy calculations with a natural product library and a diverse library set from Chembridge database. Two compounds, 14671 and 4610, were identified at the enzyme's active site and interacted with catalytic residues, Asp43, Asp44, His41, His147, His 150, Arg80 and Arg231. Both molecules exhibited stable conformation in their protein-ligand complexes with binding free energies for compound-14671 and compound-4610 of -54 ± 4 and -50 ± 4 kcal/mol, respectively. These scaffolds can be incorporated in future synthetic determinations, focusing on developing druggable inhibitor support, increasing potency, and introducing species selectivity.Communicated by Ramaswamy H. Sarma.

6.
Microb Pathog ; 164: 105404, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35065253

RESUMO

COVID-19 pandemic 2nd wave catastrophic effect in the state of Chhattisgarh, India, from where no exclusive genomic data yet published, has prompted us to undertake this study to unearth the causative variant. Whole-genome sequencing of SARS-CoV-2 isolated from COVID-19 infected nine vaccinated healthcare workers (HCW), thirty mild/moderate, seventeen severe, and twenty-seven deceased patients, was performed. The significant predominance of the SARS-CoV-2 variant of concern (VOC), Delta (lineage B.1.617.2) identified in sixty-four (77.1%) cases in contrast to B.1 and its sublineage in eleven (13.2%), variant under monitoring (VUM), Kappa (lineage B.1.617.1) in five (6.0%) and another VOC Alpha (lineage B.1.1.7) in three (3.6%) cases respectively (p < 0.05, χ2 = 162.49). 88.8% vaccine breakthrough, 60% mild/moderate, 94.4% severe and 81.5% dead patients were infected by Delta. Kappa presents exclusively in mild/moderate, Alpha in vaccine breakthrough, mild/moderate, and dead patient and B.1 and its sublineages in mild, severe, and dead patient categories. Delta variant spike mutation of T19R, G142D, E156G, L452R, and deletion (F157 and R158) helps in escaping antibody response, T478K and D614G enhance viral affinity with ACE2 receptor while P681R and D950N result in higher replication and transmissibility by cleaving S1/S2 at furin site. We conclude that Delta variant predominant role along with co-occurrence of Kappa, Alpha, and B.1 variant during COVID-19 2nd wave pandemic in Chhattisgarh may pose a potential threat of future outbreak through hybrid variant evolution. Thus, intensive genomic surveillance for monitoring variant evolution and a more efficacious vaccine against the Delta and Alpha variants are required.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , Genômica , Humanos , Mutação , Pandemias , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
7.
Microb Pathog ; 161(Pt A): 105214, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34592368

RESUMO

Plasmodium knowlesi, recognized as the fifth Plasmodium parasite, is the least studied malaria parasite. It is a significant cause of morbidity and mortality in the South-East Asia region. Enzymes of folate synthesis, especially dihydrofolate reductase (DHFR), is a well-approved drug target in other Plasmodium species, but its role in Plasmodium knowlesi is poorly studied. This work characterizes PkDHFR as a drug target and identifies inhibitors that can withstand the upcoming problem of resistance. The 3D structure of the PkDHFR target is modelled using comparative modelling, and further, it is refined and validated using energy minimization and torsional angle analysis methods. We extracted 13 compounds from DrugBank and ZINC databases using the "target similarity search" criteria. These compounds were categorized based on their binding affinity (-4.49 to -10.08 kcal/mol) and pose prediction against the active site of PkDHFR. Later on, the top 5 PkDHFR-compound complexes with high or equivalent binding affinity to its natural ligand (dihydrofolate) have undergone for dynamics. The simulation experiments reveal the higher stability of DB00563-PkDHFR complex and less conformational fluctuations and share a similar degree of compactness throughout the simulation trajectory. The MM/GBSA calculation of free energy of DB00563 is also the least (-72.84 kcal/mol) compared to others. Furthermore, the flexible side chain of DB00563 can bind and block the active site of PkDHFR more efficiently. Thus, the identified drug may be considered as a potential candidate for treating P. knowlesi malaria.


Assuntos
Malária , Plasmodium knowlesi , Humanos , Malária/tratamento farmacológico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Tetra-Hidrofolato Desidrogenase
8.
Transl Psychiatry ; 11(1): 480, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535637

RESUMO

Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.


Assuntos
Doença de Alzheimer , Transtorno do Espectro Autista , Transtorno Autístico , Doença de Alzheimer/genética , Animais , Camundongos , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso , Proteoma , Proteômica , Transdução de Sinais , Serina-Treonina Quinases TOR
9.
Mol Biol Res Commun ; 10(3): 131-140, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34476266

RESUMO

The severe acute respiratory syndrome is a viral respiratory disease recognised as COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Formerly, no precise remedies are available, and many studies regarding COVID-19 prevention and treatment are under development. Several targets for the design of drugs are identified, and studies are in headway to explore the potential target. RNA-dependent RNA polymerase (RdRp) protein identified as a promising target against SARS-CoV-2 infection for the drug design due to its significant role in viral replication. The present study focuses on identifying the binding effect of previously known RdRp inhibitors with RdRp of SARS-CoV-2 using molecular docking and molecular dynamics simulation approaches. Molecular docking and binding free energy calculations against RdRp enzyme identified suramin as a potential compound that showed the highest docking score of -7.83 Kcal/mole and binding energy of -80.83 Kcal/mole as a comparison to other compounds. Further, molecular dynamics simulation studies were moreover showed the stable binding behaviour of suramin docked complex in the protein active site. Thus, the study concludes that suramin might be helpful as a potential inhibitor against RNA-dependent RNA polymerase of SRAS-CoV-2. However, further investigation is needed to assess the possible effect of inhibitors on RdRp through in vitro and in vivo experiments.

10.
Environ Anal Health Toxicol ; 36(3): e2021020-0, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34428861

RESUMO

Methyl isocyanate (MIC), a low molecular weight synthetic aliphatic compound, having an isocyanate group (-NCO), has industrial application. In this study, the effects of methyl isocyanate and its mechanism on outer membrane protein of Escherichia coli were observed using experimental and computational methods. In vitro exposure of N-succinimidyl N-methylcarbamate (NSNM) a synthetic analogue of MIC on E. coli to a final concentration of 2 mM was found to affect the growth curve pattern and changes in cell morphology. Molecular docking studies of MIC and NSNM with E. coli outer membrane protein (OmpW, OmpX, OmpF OmpA), and periplasmic domain (PAL) were performed. The in-silico results revealed that outer membrane protein OmpF showed the highest negative binding energy, i.e. ∆G -4.11 kcal/mole and ∆G -3.19 kcal/mole by NSNM and MIC as compared to other proteins. Our study concludes that methyl isocyanate retains lethal toxicity which leads to cell death due to the membrane protein damage of E. coli membrane.

11.
Mol Divers ; 25(3): 1439-1460, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34159484

RESUMO

The accumulation of massive data in the plethora of Cheminformatics databases has made the role of big data and artificial intelligence (AI) indispensable in drug design. This has necessitated the development of newer algorithms and architectures to mine these databases and fulfil the specific needs of various drug discovery processes such as virtual drug screening, de novo molecule design and discovery in this big data era. The development of deep learning neural networks and their variants with the corresponding increase in chemical data has resulted in a paradigm shift in information mining pertaining to the chemical space. The present review summarizes the role of big data and AI techniques currently being implemented to satisfy the ever-increasing research demands in drug discovery pipelines.


Assuntos
Inteligência Artificial , Big Data , Descoberta de Drogas/métodos , Algoritmos , Bases de Dados Factuais , Aprendizado Profundo , Desenho de Fármacos , Aprendizado de Máquina , Reprodutibilidade dos Testes , Fluxo de Trabalho
12.
Bioorg Chem ; 111: 104922, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33945941

RESUMO

Novel N-Benzylpyrrolidine hybrids were designed, synthesized, and tested against multiple in-vitro and in-vivo parameters. Among all the synthesized molecules, 8f and 12f showed extensive inhibition against beta-secretase-1 (hBACE-1), human acetylcholinesterase (hAChE) & human butyrylcholinesterase (hBuChE). These molecules are also endowed with significant AChE-peripheral anionic site (PAS) binding capability, blood-brain barrier permeability, potential disassembly of Aß aggregates along with neuroprotection ability on SHSY-5Y cell lines. Results of the Y-Maze and Morris water maze test concluded that compounds 8f and 12f ameliorated cognitive dysfunction induced by scopolamine and Aß. The ex-vivo activity was executed on rat's brain homogenate indicating a reduction in AChE level and oxidative stress. The pharmacokinetic investigation ascertained considerable oral absorption profile of the lead 12f. The results of the in silico docking studies and molecular dynamics simulations demonstrated stable interactions of compounds 8f and 12f with the target residues of hAChE, hBuChE and hBACE-1.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Oxidiazóis/farmacologia , Pirrolidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxidiazóis/síntese química , Oxidiazóis/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
13.
Artigo em Inglês | MEDLINE | ID: mdl-33722765

RESUMO

The utilization of pesticides has increased for destroying pests and protecting crops in the agriculture field. Triazophos is a commonly used organophosphorous insecticide that causes alterations in haematological and histological parameters in fish. The present study was designed to evaluate the effect of triazophos induced innate and cell mediated immunotoxicity in freshwater teleost, Channa punctata. Fishes were exposed to triazophos at concentrations 5 and 10% of LC50 value for 10 and 20 days. Splenic and head kidney macrophage phagocytosis, nitric oxide production and superoxide production were assayed to evaluate the innate immunity. Cell-mediated immunity was measured through splenic and head kidney lymphocyte proliferation in presence of T and B cell mitogens. Results of the present study revealed that macrophage phagocytosis was significantly reduced after in vivo triazophos treatment. Differential suppressive effect of triazophos was also observed where mitogen induced splenic and head kidney lymphocyte proliferations were reduced after 10 and 20 days treatment. Concentration dependent effect of triazophos was observed in in vivo studies where the production of reactive oxygen and nitrogen intermediates were suppressed. This study describes the first investigation of the effect of triazophos on immune functions and will help to determine appropriate ecotoxicity and immunotoxicity in freshwater teleosts.


Assuntos
Peixes/metabolismo , Imunidade Celular/efeitos dos fármacos , Organotiofosfatos/toxicidade , Praguicidas/toxicidade , Triazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Rim Cefálico/citologia , Rim Cefálico/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Fagocitose , Baço/citologia , Baço/efeitos dos fármacos
14.
Drug Chem Toxicol ; : 1-8, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602036

RESUMO

Triazophos is a commonly used organophosphate insecticide, which inhibits the acetylcholinesterase enzyme and causes paralysis and death of insects. Impact of the pesticides on immunity has scarcely been investigated, especially in fishes. The present study was designed to analyze the immunotoxic role of in vitro triazophos exposure to the leucocytes in freshwater teleost, Channa punctatus. Triazophos, at in vitro concentrations of 0.1, 0.5, and 1 µg ml-1, was used to study leucocyte phagocytosis, superoxide production, nitrite release, and lymphocyte proliferation. Dose-dependent suppression of various immune responses was observed. Nitrite release and superoxide production by leucocytes were reduced in cultures incubated with triazophos. Mitogen-induced lymphocyte proliferation was significantly reduced at 0.5 and 1 µg ml-1 but not at 0.1 µg ml-1 concentration of pesticide. The biphasic suppressive effect was also discovered while evaluating phagocytic response. These investigations describe the effects of pesticide on immune responses in C. punctatus, which are helpful in understanding the immunotoxicity in fish. Substantially more researches are required to help design the measures to combat ecotoxicity in freshwater bodies.

15.
J Biomol Struct Dyn ; 39(15): 5668-5681, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32643552

RESUMO

SARS-CoV-2 is the causative agent of COVID-19 and has been declared as pandemic disease by World Health Organization. Lack of targeted therapeutics and vaccines for COVID-2019 have triggered the scientific community to develop new vaccines or drugs against this novel virus. Many synthetic compounds and antimalarial drugs are undergoing clinical trials. The traditional medical practitioners widely use Indian medicinal plant Withania somnifera (Ashwagandha) natural constituents, called withanolides for curing various diseases. The main protease (Mpro) of SARS-CoV-2 plays a vital role in disease propagation by processing the polyproteins which are required for its replication. Hence, it denotes a significant target for drug discovery. In the present study, we evaluate the potential of 40 natural chemical constituents of Ashwagandha to explore a possible inhibitor against main protease of SARS-CoV-2 by adopting the computational approach. The docking study revealed that four constituents of Ashwagandha; Withanoside II (-11.30 Kcal/mol), Withanoside IV (-11.02 Kcal/mol), Withanoside V (-8.96 Kcal/mol) and Sitoindoside IX (-8.37 Kcal/mol) exhibited the highest docking energy among the selected natural constituents. Further, MD simulation study of 100 ns predicts Withanoside V possess strong binding affinity and hydrogen-bonding interactions with the protein active site and indicates its stability in the active site. The binding free energy score also correlates with the highest score of -87.01 ± 5.01 Kcal/mol as compared to other selected compounds. In conclusion, our study suggests that Withanoside V in Ashwagandha may be serve as a potential inhibitor against Mpro of SARS-CoV-2 to combat COVID-19 and may have an antiviral effect on nCoV.Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Withania , Antivirais/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais , Inibidores de Proteases/farmacologia , SARS-CoV-2
16.
RSC Adv ; 11(47): 29207-29214, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35479559

RESUMO

B3LYP/cc-pV(D/T/Q)Z and CCSD/cc-pVDZ levels of theory predict three minima for both dimers and trimers of methanethiol. Predictions at B3LYP/cc-pVDZ corroborates exceedingly well with the earlier reported experimental value but significantly differ from the previous computational predictions. Interaction energy between the molecules decreases with an increase in the size of the basis set for both the dimer and trimer. The dipole moment of methanethiol dimer gets reduced at the B3LYP/cc-pVDZ level of theory relative to all minima configurations, and the same is seen for trimer also. These new predictions are well supported by atoms in molecules (AIM), frontier molecular orbital (FMO), Mulliken charge (MC), and natural bond orbital (NBO) analysis.

17.
Plant Foods Hum Nutr ; 75(4): 458-466, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33037564

RESUMO

The severe acute respiratory syndrome is a viral respiratory infection and commonly called as COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It widely transmitted through direct or indirect contact. Currently, no specific treatment against SARS-CoV-2 are available; only prevention and supportive strategy are the preventive measures. The present review emphasizes the latest research related to COVID-19 and SARS-CoV-2 virus as well as the current status of potential inhibitors identified. Recent interest in SARS-CoV-2 has focused on transmission, symptoms, structure, and its structural proteins that exhibit promising therapeutics targets for rapid identification of potential inhibitors. The quick identification of potential inhibitors and immune-boosting functional food ingredients are crucial to combat this pandemic disease. We also tried to give an overview of the functional food components as a nutritional supplement, which helps in boosting our immune system and could be useful in preventing the COVID-19 and/or to improve the outcome during therapy.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Alimento Funcional , Pandemias , Pneumonia Viral , COVID-19 , Humanos , SARS-CoV-2
18.
Sci Rep ; 10(1): 14722, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895425

RESUMO

Objectives of the current work were to investigate the role of photoperiod and melatonin in the alteration of immune responses in a reptilian species. Animals were kept on a regimen of short or long days. Blood was obtained and leucocytes were isolated to study various innate immune responses. Lymphocytes were separated from blood by density gradient centrifugation and were used to study proliferation. Respiratory burst activity was measured through nitrobluetetrazolium reduction assay while nitric oxide production by leucocytes was assayed by nitrite assay. Lymphocytes were isolated and used to study proliferation with and without B and T cell mitogens. Photoperiodic manipulation acted differentially on leucocyte counts. Nitrite release was increased while superoxide production was decreased in cultures obtained from the snakes kept on the short day regimen. Significant enhancement of mitogen induced lymphocyte proliferation was observed in cultures from the animals kept in either long or short days compared to cultures from the animals kept in natural ambient day length. Use of in vitro melatonin showed that lymphocytes from the animals, kept in long days, were more reactive. Photoperiod induces changes in immune status which may permit adaptive functional responses in order to maintain seasonal energetic budgets of the animals. Physiological responses (like elevated immune status) are energetically expensive, therefore, animals have evolved a strategy to reduce immune functions at times when energy is invested in reproductive activities. Natrix piscator breeds from September to December and elevated pineal hormone in winter suppresses reproduction while immunity is stimulated.


Assuntos
Ritmo Circadiano/imunologia , Colubridae/imunologia , Imunidade Celular/imunologia , Imunidade Inata/imunologia , Animais , Cruzamento/métodos , Proliferação de Células/fisiologia , Água Doce , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Masculino , Melatonina/imunologia , Fotoperíodo , Reprodução/imunologia , Estações do Ano
19.
J Comput Aided Mol Des ; 34(9): 983-1002, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32488355

RESUMO

The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC50 = 0.062 µM; BChE, IC50 = 1.482 µM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Aß aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Biologia Computacional/métodos , Desenho de Fármacos , Domínio Catalítico , Inibidores da Colinesterase/química , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Agregados Proteicos
20.
Redox Biol ; 34: 101567, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32464501

RESUMO

Nitric oxide (NO) is a multifunctional signalling molecule and a neurotransmitter that plays an important role in physiological and pathophysiological processes. In physiological conditions, NO regulates cell survival, differentiation and proliferation of neurons. It also regulates synaptic activity, plasticity and vesicle trafficking. NO affects cellular signalling through protein S-nitrosylation, the NO-mediated posttranslational modification of cysteine thiols (SNO). SNO can affect protein activity, protein-protein interaction and protein localization. Numerous studies have shown that excessive NO and SNO can lead to nitrosative stress in the nervous system, contributing to neuropathology. In this review, we summarize the role of NO and SNO in the progression of neurodevelopmental, psychiatric and neurodegenerative disorders, with special attention to autism spectrum disorder (ASD). We provide mechanistic insights into the contribution of NO in diverse brain disorders. Finally, we suggest that pharmacological agents that can inhibit or augment the production of NO as well as new approaches to modulate the formation of SNO-proteins can serve as a promising approach for the treatment of diverse brain disorders.


Assuntos
Transtorno do Espectro Autista , Encefalopatias , Doenças Neurodegenerativas , Transtorno do Espectro Autista/tratamento farmacológico , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Óxido Nítrico/metabolismo , Processamento de Proteína Pós-Traducional
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