Screening and Identification of Potential iNOS Inhibitors to Curtail Cervical Cancer Progression: an In Silico Drug Repurposing Approach

Abstract Cervical cancer is the second most common cause of cancer deaths in women worldwide and remains the main reason of mortality amongst women of reproductive age in developing countries. Nitric oxide is involved in several physiological functions inclusive of inflammatory and immune responses. However, the function of NO in tumor biology is debatable. The inducibleNOS (iNOS/NOS2) isoform is the oneresponsible to maintain the levels of NO and it exhibits pleotropic effects in various cancer with concentration-dependent pro- and anti-tumor effects.NOS2 triggers angiogenesis and endothelial cell migration in tumors by regulating the levels of vascular endothelial growth factor (VEGF). In drug discovery, drug repurposing involves investigations of approved drug candidates to treat various other diseases. In this study, we used FDA-approved anti-cancer drugs and small molecules to target iNOS and identify a potential selective iNOS inhibitor. The structures of ligands were geometrically optimized, and energy minimized using Hyperchem software. Molecular docking was performed using Molegro virtual docker and ligands were selected based on MolDock score,Rerank score, and H-bonding energy. In the study showed 4 compounds, Degarelix, Goserelin, Triptorelin pamoate, and venetoclax demonstrated excellent binding affinity to NOS2 protein. These compounds exhibited the lowest MolDock score, Rerank score, with better H-bonding energy to NOS2. Based on the results theses ligands project to be promising potential NOS2 inhibitors to curtail cervical cancer progression

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Drug repurposing approach for the identification and designing of potential E6 inhibitors against cervical cancer: an in silico investigation

Structural Chemistry ◽

10.1007/s11224-019-01378-x ◽

2019 ◽

Vol 31 (1) ◽

pp. 141-153 ◽

Cited By ~ 2

Author(s):

Avinash Kumar ◽

Ekta Rathi ◽

Suvarna G. Kini

Keyword(s):

Cervical Cancer ◽

In Silico ◽

Drug Repurposing

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The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323999200824115536 ◽

2020 ◽

Vol 23 ◽

Author(s):

Sisir Nandi ◽

Mohit Kumar ◽

Mridula Saxena ◽

Anil Kumar Saxena

Keyword(s):

Molecular Docking ◽

In Silico ◽

Drug Repurposing ◽

Clinical Settings ◽

The Novel ◽

In Silico Docking ◽

Biochemical Mechanisms ◽

Novel Coronavirus ◽

In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

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Exploring PLAC1 Structure and Underlying Mechanisms to Design a Derivative Vaccine Against Breast Cancer Progression; In-Silico Study

Current Proteomics ◽

10.2174/1570164617666191203111451 ◽

2020 ◽

Vol 17 (5) ◽

pp. 379-391

Author(s):

Farzaneh Afzali ◽

Parisa Ghahremanifard ◽

Mohammad Mehdi Ranjbar ◽

Mahdieh Salimi

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

In Silico ◽

Tertiary Structure ◽

Specific Antigen ◽

Docking Simulation ◽

Post Translational Modification ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Underlying Mechanisms

Background: The tolerogenic homeostasis in Breast Cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Objective: Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments. Methods and Result: The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, proteinprotein docking simulation was carried out to ensure the attachment of construct with Toll-Like Receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity. Conclusion: Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

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

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201201113712 ◽

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.

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Genistein Induces Alterations of Epigenetic Modulatory Signatures in Human Cervical Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170918142114 ◽

2018 ◽

Vol 18 (3) ◽

pp. 412-421 ◽

Cited By ~ 24

Author(s):

Madhumitha Kedhari Sundaram ◽

Mohammad Zeeshan Ansari ◽

Abdullah Al Mutery ◽

Maryam Ashraf ◽

Reem Nasab ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

In Silico ◽

Tumour Suppressor Genes ◽

Dietary Polyphenols ◽

In Silico Studies ◽

Genistein Treatment ◽

Cervical Cancer Cells ◽

Human Cervical Cancer Cells ◽

Human Cervical Cancer

Introduction: Epidemiological studies indicate that diet rich in fruits and vegetables is associated with decreased cancer risk thereby indicating that dietary polyphenols can be potential chemo-preventive agents. The reversible nature of epigenetic modifications makes them a favorable target for cancer prevention. Polyphenols have been shown to reverse aberrant epigenetic patterns by targeting the regulatory enzymes, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). In vitro and in silico studies of DNMTs and HDACs were planned to examine genistein’s role as a natural epigenetic modifier in human cervical cancer cells, HeLa. Methods: Expression of the tumour suppressor genes (TSGs) [MGMT, RARβ, p21, E-cadherin, DAPK1] as well the methylation status of their promoters were examined alongwith the activity levels of DNMT and HDAC enzymes after treatment with genistein. Expression of DNMTs and HDACs was also studied. In-silico studies were performed to determine the interaction of genistein with DNMTs and HDACs. Results: Genistein treatment significantly reduced the expression and enzymatic activity of both DNMTs and HDACs in a time-dependent way. Molecular modeling data suggest that genistein can interact with various members of DNMT and HDAC families and support genistein mediated inhibition of their activity. Timedependent exposure of genistein reversed the promoter region methylation of the TSGs and re-established their expression. Conclusions: In this study, we find that genistein is able to reinstate the expression of the TSGs studied by inhibiting the action of DNMTs and HDACs. This shows that genistein could be an important arsenal in the development of epigenetic based cancer therapy.

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LncRNA PVT1 promotes cervical cancer progression by sponging miR-503 to upregulate ARL2 expression

Open Life Sciences ◽

10.1515/biol-2021-0002 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1-13

Author(s):

Weiwei Liu ◽

Dongmei Yao ◽

Bo Huang

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Nude Mouse Model ◽

Western Blot Assay ◽

Non Coding Rna ◽

Long Non Coding Rna

Abstract Cervical cancer (CC) is a huge threat to the health of women worldwide. Long non-coding RNA plasmacytoma variant translocation 1 gene (PVT1) was proved to be associated with the development of diverse human cancers, including CC. Nevertheless, the exact mechanism of PVT1 in CC progression remains unclear. Levels of PVT1, microRNA-503 (miR-503), and ADP ribosylation factor-like protein 2 (ARL2) were measured by quantitative reverse transcription-polymerase chain reaction or western blot assay. 3-(4,5)-Dimethylthiazole-2-y1)-2,5-biphenyl tetrazolium bromide (MTT) and flow cytometry were used to examine cell viability and apoptosis, respectively. For migration and invasion detection, transwell assay was performed. The interaction between miR-503 and PVT1 or ARL2 was shown by dual luciferase reporter assay. A nude mouse model was constructed to clarify the role of PVT1 in vivo. PVT1 and ARL2 expressions were increased, whereas miR-503 expression was decreased in CC tissues and cells. PVT1 was a sponge of miR-503, and miR-503 targeted ARL2. PVT1 knockdown suppressed proliferation, migration, and invasion of CC cells, which could be largely reverted by miR-503 inhibitor. In addition, upregulated ARL2 could attenuate si-PVT1-mediated anti-proliferation and anti-metastasis effects on CC cells. Silenced PVT1 also inhibited CC tumor growth in vivo. PVT1 knockdown exerted tumor suppressor role in CC progression via the miR-503/ARL2 axis, at least in part.

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UBE2C Drives Human Cervical Cancer Progression and Is Positively Modulated by mTOR

Biomolecules ◽

10.3390/biom11010037 ◽

2020 ◽

Vol 11 (1) ◽

pp. 37

Author(s):

An-Jen Chiang ◽

Chia-Jung Li ◽

Kuan-Hao Tsui ◽

Chung Chang ◽

Yuan-chin Ivan Chang ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Cancer Staging ◽

Cervical Squamous Cell Carcinoma ◽

Cancer Cell Proliferation ◽

Gynecological Malignancy ◽

In Vivo Experiments ◽

Ubiquitin Conjugating Enzyme

Cervical cancer is a common gynecological malignancy, accounting for 10% of all gynecological cancers. Recently, targeted therapy for cervical cancer has shown unprecedented advantages. Several studies have shown that ubiquitin conjugating enzyme E2 (UBE2C) is highly expressed in a series of tumors, and participates in the progression of these tumors. However, the possible impact of UBE2C on the progression of cervical squamous cell carcinoma (CESC) remains unclear. Here, we carried out tissue microarray analysis of paraffin-embedded tissues from 294 cervical cancer patients with FIGO/TNM cancer staging records. The results indicated that UBE2C was highly expressed in human CESC tissues and its expression was related to the clinical characteristics of CESC patients. Overexpression and knockdown of UBE2C enhanced and reduced cervical cancer cell proliferation, respectively, in vitro. Furthermore, in vivo experiments showed that UBE2C regulated the expression and activity of the mTOR/PI3K/AKT pathway. In summary, we confirmed that UBE2C is involved in the process of CESC and that UBE2C may represent a molecular target for CESC treatment.

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