Screening ,development of Transglutaminase-2 Inhibitors and its derivative as anti-lung cancer agent by insilico and invitro approach

2021 ◽  
Vol 17 ◽  
Author(s):  
Prachi P. Parvatikar ◽  
Sumangala Patil ◽  
Joy Hoskeri ◽  
Sandeep Swargam ◽  
Raghvendra Kulkarni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transglutaminase 2 ◽  
Docking Studies ◽  
Target Protein ◽  
Cellular Processes ◽  
Cytotoxicity Studies ◽  
Pharmacokinetic Properties ◽  
Cancer Agent ◽  
Inhibition Property ◽  
Cancer Inhibition

Aim: Screening and development of TG2 inhibitors as anti lung cancer agent. Background: Transglutaminase 2 (TG2) is multifunctional and ubiquitously expressed protein from transglutaminase family. It takes part in various cellular processes and plays an important role in the pathogenesis of autoimmune, neurodegerative and also cancer. Background: Transglutaminase 2 (TG2) is multifunctional and ubiquitously expressed protein from transglutaminase family. It takes part in various cellular processes and plays an important role in the pathogenesis of autoimmune, neurodegerative and also cancer. Objective : The of proposed study is to focused on screening of potent inhibitors of TG2 by in-silico method and synthesis its derivative as well as analysis of its activity by invitro approach. Material and Methods: Molecular docking studies have been carried on the different classes of TG2 inhibitors against the target protein. Nearly thirty TG2 inhibitors were selected from literature and docking was performed against transglutaminase 2. The computational ADME property screening was also carried out to check their pharmacokinetic properties. The compounds which exhibited positive ADME properties with good interaction with possessing least binding energy were further validated for their anti-lung cancer inhibition property against A549 cell lines by cytotoxicity studies. Results: The results of present study indicate that the docked complex formed by cystamine showed better binding affinity towards target protein so, this derivative of cystamine is formed using 2,5 dihydrobenzoic acid. Invitro results revealed that both molecule proved good cytotoxic agent against A549 lung cancer (875.10, 553.22 µg/ml) respectively. Further its activity should be validated on TG2 expressing lung cancer. Conclusion : Cystamine and its derivative can be act as potential therapeutic target for lung cancer but further its activity should be validated on TG2 expressing lung cancer.

scholarly journals STUDY OF MAO-B INHIBITOR ANALOUGES FOR PARKINSON’S DISEASE THROUGH CADD APPROACHES

2018 ◽  
Vol 8 (5-s) ◽  
pp. 240-250
Author(s):  
Manish Bachhar ◽  
BK Singh
Keyword(s):  
Molecular Design ◽  
Neurodegenerative Disorder ◽  
Binding Mode ◽  
Docking Studies ◽  
Target Protein ◽  
Binding Affinities ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Mao B ◽  
Pharmacokinetic Properties

New derivatives are designed as target directed MAO-B Inhibitors for medical care of the patients for neurodegenerative disorder. Molecular design and estimated pharmacokinetic properties have been evaluated by using Inventus v 1.1 software. The binding mode of the proposed compounds with target protein i.e. 1S2Q was evaluated and the resulting data from docking studies explained that newly designed derivatives have high and better affinity towards target protein. Based on these properties, the binding affinities are used for speeding up drug discovery process by eliminating less potent compounds from synthesis. Keywords: MAO-B, Inventus, Target protein, Neurodegenerative, Docking.

scholarly journals GC–MS Analysis, Molecular Docking and Pharmacokinetic Properties of Phytocompounds from Solanum torvum Unripe Fruits and Its Effect on Breast Cancer Target Protein

2021 ◽  
Author(s):  
R. Saravanan ◽  
K. Raja ◽  
D. Shanthi
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Studies ◽  
Target Protein ◽  
Solanum Torvum ◽  
Ms Analysis ◽  
Pharmacokinetic Properties ◽  
Synthetic Drug ◽  
Unripe Fruits

Abstract This study was designed to identify phytocompounds from the aqueous extract of Solanum torvum unripe fruits using GC–MS analysis against breast cancer. For this, the identified phytocompounds were subjected to perform molecular docking studies to find the effects on breast cancer target protein. Pharmacokinetic properties were also tested for the identified phytocompounds to evaluate the ADMET properties. Molecular docking studies were done using docking software PyRx, and pharmacokinetic properties of phytocompounds were evaluated using SwissADME. From the results, ten best compounds were identified from GC–MS analysis against breast cancer target protein. Of which, three compounds showed very good binding affinity with breast cancer target protein. They are ergost-25-ene-3,6-dione,5,12-dihydroxy-,(5.alpha.,12.beta.) (− 7.3 kcal/mol), aspidospermidin-17-ol,1-acetyl-16-methoxy (− 6.7 kcal/mol) and 2-(3,4-dichlorophenyl)-4-[[2-[1-methyl-2-pyrrolidinyl]ethyl amino]-6-[trichloromethyl]-s-triazine (− 6.7 kcal/mol). Further, docking study was performed for the synthetic drug doxorubicin to compare the efficiency of phytocompounds. The binding affinity of ergost-25-ene-3,6-dione,5,12-dihydroxy-,(5.alpha.,12.beta.) is higher than the synthetic drug doxorubicin (− 7.2 kcal/mol), and the binding affinity of other compounds is also very near to the drug. Hence, the present study concludes that the phytocompounds from the aqueous extract of Solanum torvum unripe fruits have the potential ability to treat breast cancer.

Drug repurposing using similarity-based target prediction, docking studies and scaffold hopping of lefamulin

2020 ◽  
Vol 17 ◽  
Author(s):  
Shikha Sharma ◽  
Shweta Sharma ◽  
Vaishali Pathak ◽  
Parwinder Kaur ◽  
Rajesh Kumar Singh
Keyword(s):  
In Silico ◽  
Target Prediction ◽  
Drug Repurposing ◽  
Docking Studies ◽  
Target Protein ◽  
Future Perspective ◽  
Antibacterial Drug ◽  
Scaffold Hopping ◽  
Target Proteins ◽  
Renin Inhibitors

Aim: To investigate and validate the potential target proteins for drug repurposing of newly FDA approved antibacterial drug. Background: Drug repurposing is the process of assigning indications for drugs other than the one(s) that they were initially developed for. Discovery of entirely new indications from already approved drugs is highly lucrative as it minimizes the pipeline of the drug development process by reducing time and cost. In silico driven technologies made it possible to analyze molecules for different target proteins which are not yet explored. Objective: To analyze possible targets proteins for drug repurposing of lefamulin and their validation. Also, in silico prediction of novel scaffolds from lefamulin has been performed for assisting medicinal chemists in future drug design. Methods: A similarity-based prediction tool was employed for predicting target protein and further investigated using docking studies on PDB ID: 2V16. Besides, various in silico tools were employed for prediction of novel scaffolds from lefamulin using scaffold hopping technique followed by evaluation with various in silico parameters viz., ADME, synthetic accessibility and PAINS. Results: Based on the similarity and target prediction studies, renin is found as the most probable target protein for lefamulin. Further, validation studies using docking of lefamulin revealed the significant interactions of lefamulin with the binding pocket of the target protein. Also, three novel scaffolds were predicted using scaffold hopping technique and found to be in the limit to reduce the chances of drug failure in the physiological system during the last stage approval process. Conclusion: To encapsulate the future perspective, lefamulin may assist in the development of the renin inhibitors and, also three possible novel scaffolds with good pharmacokinetic profile can be developed into both as renin inhibitors and for bacterial infections.

scholarly journals Nuclear Transglutaminase 2 interacts with topoisomerase II⍺ to promote DNA damage repair in lung cancer cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xiao Lei ◽  
Kun Cao ◽  
Yuanyuan Chen ◽  
Hui Shen ◽  
Zhe Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Protein Localization ◽  
Transglutaminase 2 ◽  
Lung Cancer Cells ◽  
Mass Spectrometry Analysis ◽  
Cancer Resistance ◽  
Dsb Repair

Abstract Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

BODIPY-peptide conjugate: Synthesis, photo-physical and cell viability studies

2021 ◽  
pp. A-J
Author(s):  
Jaydeepsinh Chavda ◽  
Krishna Bhavsar ◽  
Sharad Gupta ◽  
Iti Gupta
Keyword(s):  
Lung Cancer ◽  
Cell Viability ◽  
Stokes Shift ◽  
Cancer Cell Line ◽  
Docking Studies ◽  
Lung Cancer Cell Line ◽  
Lung Cancer Cell ◽  
Standard Drug ◽  
Biological Studies ◽  
Lung Cancer A549 Cell

The synthesis and biological studies of BODIPY-GPR peptide conjugate (BD-2) are reported. As compared to the parent BODIPY (BD-1), the peptide linked BD-2showed blue shifted absorption and emission with excellent Stokes shift of 201 nm. Molecular docking studies on EGFR protein kinase indicated very efficient binding affinity of BD-2 as compared to the standard drug (Erlotinib). The cell viability experiments of BD-2on normal (HEK293T) and lung cancer (A549) cell lines indicated 85–95% viability. Bioimaging studies showed that, BD-2was able to penetrate the lung cancer cell line.

scholarly journals Inhibiting TG2 sensitizes lung cancer to radiotherapy through interfering TOPOIIα-mediated DNA repair

2019 ◽  
Author(s):  
Xiao Lei ◽  
Zhe Liu ◽  
Kun Cao ◽  
Yuanyuan Chen ◽  
Jianming Cai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Dna Repair ◽  
Transglutaminase 2 ◽  
Small Cell ◽  
Small Cell Lung ◽  
Poor Survival ◽  
Novel Approaches

AbstractRadiotherapy is an indispensable strategy for lung cancer, however, treatment failure or reoccurrence is often found in patients due to the developing radioresistance. Novel approaches are required for radiosensitizing to improve the therapeutic efficacy. In present study, we found that transglutaminase 2 (TG2) confers radioresistance in non-small cell lung cancer (NSCLC) cells through regulating TOPOIIα and promoting DNA repair. Our data showed that TG2 inhibitor or knockdown increased NSCLC radiosensitivity in vivo and in vitro. We found that TG2 translocated into nucleus and located to DSB sites, surprisingly, knockdown TG2 or glucosamine inhibited the phosphorylation of ATM, ATR and DNA-Pkcs. Through IP-MS assay and functional experiments, we identified that TOPOIIα as an downstream factor of TG2. Moreover, we found that TGase domain account for the interaction with TOPOIIα. Finally, we found that TG2 expression was correlated with poor survival in lung adenocarcinoma instead of squamous cell carcinoma. In conclusion, we demonstrated that inhibiting TG2 sensitize NSCLC to IR through interfere TOPOIIα mediated DNA repair, suggesting TG2 as a potential radiosensitizing target in NSCLC.

scholarly journals Transglutaminase 2 Promotes Migration and Invasion of Lung Cancer Cells

2018 ◽  
Vol 26 (8) ◽  
pp. 1175-1182 ◽  
Author(s):  
Hung-Tsung Lee ◽  
Cheng-Hsieh Huang ◽  
Wuan-Chun Chen ◽  
Chi-Shan Tsai ◽  
Yu-Lin Chao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Transglutaminase 2 ◽  
Lung Cancer Cells ◽  
Migration And Invasion

Computational Investigation of Versatile Activity of Piperine

2019 ◽  
pp. 127-139
Author(s):  
Thenmozhi Marudhadurai ◽  
Navabshan Irfan
Keyword(s):  
Docking Study ◽  
Black Pepper ◽  
Docking Studies ◽  
Therapeutic Activity ◽  
Computational Docking ◽  
Target Proteins ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Anti Oxidant ◽  
Inhibition Property

Piperine is known for its versatile therapeutic activity. It has been used for various disease conditions (e.g., cold, cough, etc.). Piperine is an alkaloid found in black pepper. It possesses various pharmacological actions like anti-inflammatory, anti-oxidant, anti-cholinergic, and anti-cancerous. The above-mentioned properties will be studied by selecting target proteins COX-2 protein, angiotensin converting enzyme, acetylcholineesterases, and survivin using computational docking study. This chapter explains the inhibition property of piperine against selected target protein from the results of docking studies. Based on the docking scores and protein-ligand interactions, piperine was found to bind well in the active site of the selected target proteins. It ensures the binding efficacy of piperine against selected target proteins. Docking scores and protein-ligand interactions plays an important role in its therapeutic activity.

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