Pharmaceutical Sciences and Natural Products - Research Publications
Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56
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Item Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors(John Wiley and Sons Inc, 2023-10-12T00:00:00) Singh, Ankit Kumar; Kumar, Adarsh; Arora, Sahil; Kumar, Raj; Verma, Amita; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, PradeepHuman immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART). � 2023 John Wiley & Sons Ltd.Item PROTAC�ing oncoproteins: targeted protein degradation for cancer therapy(BioMed Central Ltd, 2023-03-30T00:00:00) Kelm, Jeremy M.; Pandey, Deepti S.; Malin, Evan; Kansou, Hussein; Arora, Sahil; Kumar, Raj; Gavande, Navnath S.Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.Item Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities(American Chemical Society, 2023-02-22T00:00:00) Maity, Pritam; Chatterjee, Joydeep; Patil, Kiran T.; Arora, Sahil; Katiyar, Madhurendra K.; Kumar, Manvendra; Samarbakhsh, Amirreza; Joshi, Gaurav; Bhutani, Priyadeep; Chugh, Manoj; Gavande, Navnath S.; Kumar, RajEpidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality. � 2023 American Chemical Society.Item FDA approved six-membered ring fused pyrimidine-based derivatives(Elsevier, 2022-10-14T00:00:00) Arora, Sahil; Kumar, RajPyrimidine-based derivatives play a vital role in the development of drugs due to their indispensable role in various biological processes. To date, ring fused pyrimidine-based derivatives have been reported to exhibit numerous biological activities including anticancer, antiviral, antianginal, anti-HIV, antifungal, antibacterial, anti-inflammatory, antitubercular and many others. There are numerous synthetic approaches available for the synthesis of fused pyrimidine-based derivatives which provides ample scope in the development of new drugs. Considering these medicinal attributes of fused pyrimidine-based derivatives, we have put forth this book chapter mainly focusing on the FDA approved six-membered ring fused pyrimidine-based derivatives. The present chapter deals with improved synthetic schemes, their biological importance and the adverse effects of FDA approved six-membered ring fused pyrimidine-based drugs. Covering all these aspects may lighten the researchers with the updated literature exploring the best synthetic routes and can think of alternative synthetic routes with less time consuming and non-toxic solvents. � 2023 Elsevier Ltd. All rights reserved.Item Pore-forming proteins and their role in cancer and inflammation: Mechanistic insights and plausible druggable targets(Elsevier Ireland Ltd, 2022-08-30T00:00:00) Sankar, Jishnu; Arora, Sahil; Joshi, Gaurav; Kumar, RajPerforin is a granular effector pore-forming protein formed in NK cells and Cytotoxic T lymphocytes. These cytotoxic proteins are part of the first-line immune defense in the human body. They ensure apoptosis of pathogen-infected cells or tumor cells in the human body. Activation of receptors on NK cell or T cell triggers secondary proteins in these cells. Further, it leads to Ca2+ dependent perforin egress towards the target cell, ensued by PI3K signaling pathway. Perforin undergoes oligomerization over the target cell membrane and forms transmembrane pores with the membrane-spanning domain-MACPF domain. Granzymes, proapoptotic serine proteases are released through these pores and initiate the target cell apoptotic pathway leading to the cell death. Although perforin is a savior for humans from tumor and viral infections, uncontrolled expression of the perforins leads to the autoimmune conditions, including Familial Hemophagocytic lymphohistiocytosis, insulin-dependent diabetes, and cerebral myocarditis. The present review is the concerted effort to highlight the mechanistic pathways concerning perforin secretion, NK cell and T cell-mediated cytotoxicity towards virus-infected and transformed cells. This is followed by the discussion on synthetic derivatives tested so far to inhibit the perforin in pre and clinical arena for certain unusual conditions. � 2022 Elsevier B.V.Item Synthetic strategies and pharmacological activities of chromene and its derivatives: An overview(Elsevier B.V., 2022-04-07T00:00:00) Katiyar, Madhurendra K.; Dhakad, Govind Kumar; Shivani; Arora, Sahil; Bhagat, Srikant; Arora, Taruna; Kumar, RajChromene is commonly found in nature and is considered one of the most frequently used scaffolds in heterocyclic chemistry for the designing of chemical probes for therapeutic and diagnostic purposes. The chromene nucleus comprises an oxine ring fused with a phenyl ring. Owing to existing several useful biological applications of chromenes have generated wide interest among chemists to synthesize its derivatives frequently. Here, in this review, we have compiled and analysed various recently reported synthetic strategies of chromene and its derivatives through numerous approaches such as microwave-assisted, catalyst based, green solvents, solvent-free conditions, etc. along with their biological applications such as anticancer, antimicrobial, anti-inflammatory, AChE inhibition, antiviral, and antioxidant activities. � 2022 Elsevier B.V.Item A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2(American Chemical Society, 2021-11-02T00:00:00) Arora, Sahil; Joshi, Gaurav; Chaturvedi, Anuhar; Heuser, Michael; Patil, Santoshkumar; Kumar, RajThe allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer�tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity. � 2021 American Chemical SocietyItem Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines(Academic Press Inc., 2021-11-01T00:00:00) Yadav, Umesh Prasad; Ansari, Arshad J.; Arora, Sahil; Joshi, Gaurav; Singh, Tashvinder; Kaur, Harsimrat; Dogra, Nilambra; Kumar, Raj; Kumar, Santosh; Sawant, Devesh M.; Singh, SandeepA series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC50 values ranging from 1 to 5.5 ?M. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase II? inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression. � 2021 Elsevier Inc.Item Rationalization of the activity Profile of Pyruvate Kinase Isozyme M2 (PKM2) Inhibitors using 3D QSAR(Bentham Science Publishers, 2021-08-05T00:00:00) Kusuma, Merugumala; Arora, Sahil; Kalra, Sourav; Chaturvedi, Anuhar; Heuser, Michael; Kumar, RajIntroduction: Pyruvate kinase isozyme M2 (PKM2) was observed to be overexpressed and play a key role in cell growth and cancer cells' metabolism. During the past years, phytochemicals have been developed as new treatment options for chemoprevention and cancer therapy. Natural re-sources, like shikonin (naphthoquinone) and its derivatives, have emerged to be high potential therapeutics in cancer treatment. Methods: Our study aimed to design novel anti-tumour agents (PKM2 inhibitors) focusing on the shikonin scaffold with a better activity using computational methods. We applied a three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using Field-based QSAR. Results: The Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of forty shikonin derivatives, including shikonin, to develop robust models and rationalize the PKM2 inhibitory activity profile by building a correlation between structural features and activity. Conclusion: These predictive computational models will further help the design and synthesis of potent PKM2 inhibitors and their fast biological assessment at a low cost. � 2021 Bentham Science Publishers.Item Synthesis of 1,4-dihydropyrazolo[4,3-b]indoles via intramolecular C(sp2)-N bond formation involving nitrene insertion, DFT study and their anticancer assessment(Academic Press Inc., 2021-06-29T00:00:00) Kaur, Manpreet; Mehta, Vikrant; Abdullah Wani, Aabid; Arora, Sahil; Bharatam, Prasad V.; Sharon, Ashoke; Singh, Sandeep; Kumar, RajWe herein report a new synthetic route for a series of unreported 1,4-dihydropyrazolo[4,3-b]indoles (6�8) via deoxygenation of o-nitrophenyl-substituted N-aryl pyrazoles and subsequent intramolecular (sp2)-N bond formation under microwave irradiation expedite modified Cadogan condition. This method allows access to NH-free as well as N-substituted fused indoles. DFT study and controlled experiments highlighted the role of nitrene insertion as one of the plausible reaction mechanisms. Furthermore, the target compounds exhibited cytotoxicity at low micromolar concentration against lung (A549), colon (HCT-116), and breast (MDA-MB-231, and MCF-7) cancer cell lines, induced the ROS generation and altered the mitochondrial membrane potential of highly aggressive MDA-MB-231 cells. Further investigations revealed that these compounds were selective Topo I (6h) or Topo II (7a, 7b) inhibitors. � 2021 Elsevier Inc.