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1.
Bioorg Chem ; 91: 103138, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446329

RESUMO

In the designed research work, a series of 2-furoyl piperazine based sulfonamide derivatives were synthesized as therapeutic agents to target the Alzheimer's disease. The structures of the newly synthesized compounds were characterized through spectral analysis and their inhibitory potential was evaluated against butyrylcholinesterase (BChE). The cytotoxicity of these sulfonamides was also ascertained through hemolysis of bovine red blood cells. Furthermore, compounds were inspected by Lipinki Rule and their binding profiles against BChE were discerned by molecular docking. The protein fluctuations in docking complexes were recognized by dynamic simulation. From our in vitro and in silico results 5c, 5j and 5k were identified as promising lead compounds for the treatment of targeted disease.

2.
Int J Neurosci ; 129(7): 666-680, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30422726

RESUMO

AIM: Amyloid beta (Aß) 1-42, which is a basic constituent of amyloid plaques, binds with extracellular transmembrane receptor nicotine acetylcholine receptor α7 (nAChRα7) in Alzheimer's disease. MATERIALS AND METHODS: In the current study, a computational approach was employed to explore the active binding sites of nAChRα7 through Aß 1-42 interactions and their involvement in the activation of downstream signalling pathways. Sequential and structural analyses were performed on the extracellular part of nAChRα7 to identify its core active binding site. RESULTS: Results showed that a conserved residual pattern and well superimposed structures were observed in all nAChRs proteins. Molecular docking servers were used to predict the common interactive residues in nAChRα7 and Aß1-42 proteins. The docking profile results showed some common interactive residues such as Glu22, Ala42 and Trp171 may consider as the active key player in the activation of downstream signalling pathways. Moreover, the signal communication and receiving efficacy of best-docked complexes was checked through DynOmic online server. Furthermore, the results from molecular dynamic simulation experiment showed the stability of nAChRα7. The generated root mean square deviations and fluctuations (RMSD/F), solvent accessible surface area (SASA) and radius of gyration (Rg) graphs of nAChRα7 also showed its backbone stability and compactness, respectively. CONCLUSION: Taken together, our predicted results intimated the structural insight on the molecular interactions of beta amyloid protein involved in the activation of nAChRα7 receptor. In future, a better understanding of nAChRα7 and their interconnected proteins signalling cascade may be consider as target to cure Alzheimer's disease.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Receptor Nicotínico de Acetilcolina alfa7/química , Sítios de Ligação , Humanos , Ligação Proteica , Domínios Proteicos , Análise de Sequência de Proteína , Transdução de Sinais
3.
Front Comput Neurosci ; 12: 34, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29910719

RESUMO

The design of novel inhibitors to target BACE1 with reduced cytotoxicity effects is a promising approach to treat Alzheimer's disease (AD). Multiple clinical drugs and antibodies such as AZD3293 and Solanezumab are being tested to investigate their therapeutical potential against AD. The current study explores the binding pattern of AZD3293 and Solanezumab against their target proteins such as ß-secretase (BACE1) and mid-region amyloid-beta (Aß) (PDBIDs: 2ZHV & 4XXD), respectively using molecular docking and dynamic simulation (MD) approaches. The molecular docking results show that AZD3293 binds within the active region of BACE1 by forming hydrogen bonds against Asp32 and Lys107 with distances 2.95 and 2.68 Å, respectively. However, the heavy chain of Solanezumab interacts with Lys16 and Asp23 of amyloid beta having bond length 2.82, 2.78, and 3.00 Å, respectively. The dynamic cross correlations and normal mode analyses show that BACE1 depicted good residual correlated motions and fluctuations, as compared to Solanezumab. Using MD, the Root Mean Square Deviation and Fluctuation (RMSD/F) graphs show that AZD3293 residual fluctuations and RMSD value (0.2 nm) was much better compared to Solanezumab (0.7 nm). Moreover, the radius of gyration (Rg) results also depicts the significance of AZD3293 docked complex compared to Solanezumab through residual compactness. Our comparative results show that AZD3293 is a better therapeutic agent for treating AD than Solanezumab.

4.
Neurol Sci ; 39(8): 1361-1374, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29789968

RESUMO

Cas scaffolding protein family member 4 and protein tyrosine kinase 2 are signaling proteins, which are involved in neuritic plaques burden, neurofibrillary tangles, and disruption of synaptic connections in Alzheimer's disease. In the current study, a computational approach was employed to explore the active binding sites of Cas scaffolding protein family member 4 and protein tyrosine kinase 2 proteins and their significant role in the activation of downstream signaling pathways. Sequential and structural analyses were performed on Cas scaffolding protein family member 4 and protein tyrosine kinase 2 to identify their core active binding sites. Molecular docking servers were used to predict the common interacting residues in both Cas scaffolding protein family member 4 and protein tyrosine kinase 2 and their involvement in Alzheimer's disease-mediated pathways. Furthermore, the results from molecular dynamic simulation experiment show the stability of targeted proteins. In addition, the generated root mean square deviations and fluctuations, solvent-accessible surface area, and gyration graphs also depict their backbone stability and compactness, respectively. A better understanding of CAS and their interconnected protein signaling cascade may help provide a treatment for Alzheimer's disease. Further, Cas scaffolding protein family member 4 could be used as a novel target for the treatment of Alzheimer's disease by inhibiting the protein tyrosine kinase 2 pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Simulação de Acoplamento Molecular , Dinâmica não Linear , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Sítios de Ligação , Feminino , Quinase 1 de Adesão Focal/química , Humanos , Masculino , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais
5.
Mol Med Rep ; 18(1): 639-655, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29845262

RESUMO

Alzheimer's disease (AD) is a complex and multifactorial disease. In order to understand the genetic influence in the progression of AD, and to identify novel pharmaceutical agents and their associated targets, the present study discusses computational modeling and biomarker evaluation approaches. Based on mechanistic signaling pathway approaches, various computational models, including biochemical and morphological models, are discussed to explore the strategies that may be used to target AD treatment. Different biomarkers are interpreted on the basis of morphological and functional features of amyloid ß plaques and unstable microtubule­associated tau protein, which is involved in neurodegeneration. Furthermore, imaging and cerebrospinal fluids are also considered to be key methods in the identification of novel markers for AD. In conclusion, the present study reviews various biochemical and morphological computational models and biomarkers to interpret novel targets and agonists for the treatment of AD. This review also highlights several therapeutic targets and their associated signaling pathways in AD, which may have potential to be used in the development of novel pharmacological agents for the treatment of patients with AD. Computational modeling approaches may aid the quest for the development of AD treatments with enhanced therapeutic efficacy and reduced toxicity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Simulação por Computador , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Biomarcadores , Biologia Computacional , Progressão da Doença , Humanos
6.
Iran J Parasitol ; 9(1): 37-43, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25642258

RESUMO

BACKGROUND: Malaria is well known for its fatalities worldwide, Plasmodium vivax and the Plasmodium falciparum are the two important species of malaria reported from Pakistan and creating lots of morbidities across the country. METHOD: Study was conducted to determine the Surveillance of malaria in South Punjab by microscopy and Polymerase chain reaction (PCR). RESULT: samples out of 100 patients were found positive for malarial parasites. One patient was found with mixed infection, whereas P. falciparum and P. vivax infections were detected in 17 and 22 patients, respectively. In nested PCR, genus-specific primers for Plasmodium species. in round 1 and species-specific primers for P. falciparum and P. vivax in round 2 were used. By the application of PCR 41% were found to be infected by Plasmodium spp. Among Plasmodium positive patients: mixed, P. falciparum and P. vivax infection were detected in 10, 15 and 16 patients, respectively. Thirty nine microscopically positive patients confirmed to have Plasmodium spp. One negative by PCR, 2 microscopically negative patients had shown Plasmodium spp. infection (P. falciparum and P. vivax) by PCR. In total samples, P. falciparum, P. vivax and mixed infection accounted for 36.6%, 39.0% and 24.3%, respectively. CONCLUSION: Microscopy was found deficient for interpretation of mixed infections, low parasitaemia, and species specific diagnosis. The sensitivity, specificity and efficacy of nested PCR was calculated 95%, 98% and 97%, respectively, showing PCR as a more effective and efficient diagnostic tool for malaria.

7.
Asian Pac J Cancer Prev ; 13(7): 3349-55, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22994759

RESUMO

BACKGROUND AND OBJECTIVES: Chromosomal abnormalities play an important role in genesis of acute lymphoblastic leukemia (ALL) and have prognostic implications. Five major risk stratifying fusion genes in ALL are BCR-ABL, MLL-AF4, ETV6-RUNX11, E2A-PBX1 and SIL-TAL1. This work aimed to detect common chromosomal translocations and associated fusion oncogenes in adult ALL patients and study their relationship with clinical features and treatment outcome. METHODS: We studied fusion oncogenes in 104 adult ALL patients using RT-PCR and interphase-FISH at diagnosis and their association with clinical characteristics and treatment outcome. RESULTS: Five most common fusion genes i.e. BCR-ABL (t 9; 22), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (Del 1p32) were found in 82/104 (79%) patients. TCF3-PBX1 fusion gene was associated with lymphadenopathy, SIL-TAL positive patients had frequent organomegaly and usually presented with a platelets count of less than 50 x10(9)/l. Survival of patients with fusion gene ETV6-RUNX1 was better when compared to patients harboring other genes. MLL-AF4 and BCR-ABL positivity characterized a subset of adult ALL patients with aggressive clinical behaviour and a poor outcome. CONCLUSIONS: This is the first study from Pakistan which investigated the frequency of 5 fusion oncogenes in adult ALL patients, and their association with clinical features, treatment response and outcome. Frequencies of some of the oncogenes were different from those reported elsewhere and they appear to be associated with distinct clinical characteristics and treatment outcome. This information will help in the prognostic stratification and risk adapted management of adult ALL patients.


Assuntos
Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Plaquetas/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Homeodomínio/genética , Humanos , Doenças Linfáticas/genética , Doenças Linfáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Paquistão , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Prognóstico , Translocação Genética/genética , Resultado do Tratamento , Adulto Jovem
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