Pharmaceutical Sciences and Natural Products - Research Publications
Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56
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Item Identification of 1,3,4-oxadiazoles as tubulin-targeted anticancer agents: a combined field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, molecular dynamics simulation, and density functional theory calculation approach(Taylor and Francis Ltd., 2023-09-11T00:00:00) Das, Agnidipta; Sarangi, Manaswini; Jangid, Kailash; Kumar, Vijay; Kumar, Amit; Singh, Praval Pratap; Kaur, Kamalpreet; Kumar, Vinod; Chakraborty, Sudip; Jaitak, VikasCancer is one of the most prominent causes of death worldwide and tubulin is a crucial protein of cytoskeleton that maintains essential cellular functions including cell division as well as cell signalling, that makes an attractive drug target for cancer drug development. 1,3,4-oxadiazoles disrupt microtubule causing G2-M phase cell cycle arrest and provide anti-proliferative effect. In this study, field-based 3D-QSAR models were developed using 62 bioactive anti-tubulin 1,3,4-oxadiazoles. The best model characterized by PLS factor 7 was rigorously validated using various statistical parameters. Generated 3D-QSAR model having high degree of confidence showed favourable and unfavourable contours around 1,3,4-oxadiazole core that assisted in defining proper spatial positioning of desired functional groups for better bioactivity. A five featured pharmacophore model (AAHHR_1) was developed using same ligand library and validated through enrichment analysis (BEDROC160.9 value = 0.59, Average EF 1% = 27.05, and AUC = 0.74). Total 30,212 derivatives of 1,3,4-oxadiazole obtained from PubChem database was prefiltered through validated pharmacophore model and docked in XP mode on binding cavity of tubulin protein (PDB code: 1SA0) which led into the identification of 11 HITs having docking scores between ?7.530 and ?9.719 kcal/mol while the reference compound Colchicine exerted docking score of ?7.046 kcal/mol. Following the analysis of MM-GBSA and ADME studies, HIT1 and HIT4 emerged as the two promising hits. To verify their thermodynamic stability at the target site, molecular dynamic simulations were carried out. Both HITs were further subjected to DFT analysis to determine their HOMO-LUMO energy gap for ensuring their biological feasibility. Finally, molecular docking based structural exploration for 1,3,4-oxadiazoles to set up a lead of Formula I for further advancements of tubulin polymerization inhibitors as anti-cancer agents. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Impact of cannabinoid receptors in the design of therapeutic agents against human ailments(Bentham Science Publishers, 2023-05-03T00:00:00) Kumar, Ankush; Gupta, Ojasvi; Bhatia, Rohit; Monga, VikramdeepThe Cannabinoid (CB) signalling cascade is widely located in the human body and is associated with several pathophysiological processes. The endocannabinoid system comprises cannabinoid receptors CB1 and CB2, which belong to G-protein Coupled Receptors (GPCRs). CB1 receptors are primarily located on nerve terminals, prohibiting neurotransmitter release, whereas CB2 are present predominantly on immune cells, causing cytokine release. The activation of CB system contributes to the development of several diseases which might have lethal consequences, such as CNS disorders, cancer, obesity, and psychotic disorders on human health. Clinical evidence revealed that CB1 receptors are associated with CNS ailments such as Alzheimer�s disease, Huntington�s disease, and multiple sclerosis, whereas CB2 receptors are primarily connected with immune disorders, pain, inflammation, etc. Therefore, cannabinoid receptors have been proved to be promising targets in therapeutics and drug discovery. Experimental and clinical outcomes have disclosed the success story of CB antagonists, and several research groups have framed newer compounds with the binding potential to these receptors. In the presented review, we have summarized variously reported heterocycles with CB receptor agonistic/antagonistic properties against CNS disorders, cancer, obesity, and other complications. The structural activity relationship aspects have been keenly described along with enzymatic assay data. The specific outcomes of molecular docking studies have also been highlighted to get insights into the binding patterns of the molecules to CB receptors. � 2023 Bentham Science Publishers.Item Synthetic Methodologies and SAR of Quinazoline Derivatives as PI3K Inhibitors(Bentham Science Publishers, 2023-01-19T00:00:00) Raj, Aditya; Kumar, Adarsh; Singh, Ankit Kumar; Singh, Harshwardhan; Thareja, Suresh; Kumar, PradeepPI3K is an important anticancer target as it controls cellular functions such as growth, transformation, pro-liferation, motility and differentiation. Plasma cell cancer (multiple myeloma) occurs more than 10% among all haema-tological malignancies and accounts for 2% of all cancer-related deaths each year, it is mainly regulated by PI3K/AKT signaling cascade. Quinazoline derivatives have been reported as promising PI3K inhibitors. Lapatinib, afatinib, ge-fitinib, erlotinib, idelalisib and copanlisib are quinazoline-based, FDA-approved PI3K inhibitors, while compounds like NVPBYL719, GDC-0032, AZD8186, AZD-6482, etc. are under different stages of clinical trials. In light of the above-mentioned facts, in the present study, we have reported different synthetic approaches, mechanisms of anticancer action, and structure-activity relationship analysis of reported quinazoline derivatives as PI3K inhibitors to help researchers working in the field in designing better and isoform-selective PI3K inhibitors. � 2023 Bentham Science Publishers.Item Flavonoids as P-glycoprotein inhibitors for multidrug resistance in cancer: an in-silico approach(Taylor and Francis Ltd., 2022-09-19T00:00:00) Kumar, Amit; Kalra, Sourav; Jangid, Kailash; Jaitak, VikasCancer has become a leading cause of mortality due to non-communicable diseases after cardiovascular disease worldwide and is increasing day by day at a daunting pace. According to an estimate by 2040 there will be 28.4 million cancer cases. Occurrence of multidrug resistance has further worsened the scenario of available cancer treatment. Among different mechanisms of multidrug resistance efflux of xenobiotics by ABC transporter is of prime importance. P-glycoprotein (P-gp) is the major factor behind occurrence of multidrug resistance due to its wide distribution and invariably big binding cavity. Various generations of chemical inhibitors for P-gp have been designed and tested are not devoid of major side effects. Thus, in present study flavonoids a major class of natural compounds was virtually screened in order to find molecules which can be used as selective P-gp inhibitors to be used along with chemotherapeutics. After screening 4275 molecules from different classes of flavonoids i.e. flavan, flavanol, flavonone, flavone, anthocyanins, and isoflavone, through Glide docking top ten hit molecules were selected based on their binding affinity, binding energy calculation and pharmacokinetic properties. All the hit molecules were found to have docking score within the range of ?11.202 to ?9.699 kcal/mol showing very strong interaction with the amino acid residues of binding pocket. Whereas, dock score of standard P-gp inhibitor verapamil was ?4.984 kcal/mol. The ligand and protein complex were found to be quite stable while run through molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.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 PARP-1 Inhibitors Reported During the Last Decade(Bentham Science Publishers, 2022-06-16T00:00:00) Guleria, Maneesh; Kumar, Pradeep; Thareja, SureshBackground: Cancer is the world's second-largest cause of death, and is responsible for an estimated 9.6 milion mortality cases in 2018. Poly-ADP-ribose polymerases (PARPs) are enzymes and a family of proteins involved in many Cellular processes, including DNA repair, gene regulation, chromatin remodeling, and apoptosis. The first characterized and best-known member of the PARP family is poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 is a major protein for DNA single-strand breaks in the BER pathway (base excision repair) (SSBs). Objective: The objective of this article was to compile synthetic PARP-1 inhibitors reported in the last decade. Methods: In the present manuscript, bibliographic investigation was carried out by scrutinizing peerreviewed articles from online/offline databases. The inclusion criteria consisted of the most relevant studies indicating the relationship between PARP-1 and cancer in textbooks/edited books and peer-reviewed papers from scientific databases, like SCOPUS, PUBMED, NISCAIR, and Google Scholar since 2010 to 2020. Only the studies published in English language were searched/considered. The exclusion criteria consisted of the studies on other PARP isoforms than PARP-1. The studies thus obtained were classified according to the heterocyclic moieties, year of publication, etc. The data compiled in this article is a systematic review of the reported studies. Results: The literature reports indicated that a number of PARP-1 inhibitors reported have IC50 value in nanomolar concentration. Conclusion: PARP-1 is an essential target for anti-cancer drug discovery. Further research on more effective and safe PARP-1 inhibitors needs to be carried out, and we may discover some novel PARP-1 inhibitors in the near future. � 2023 Bentham Science Publishers.Item Molecular dynamics and 3D-QSAR studies on indazole derivatives as HIF-1? inhibitors(Taylor and Francis Ltd., 2022-03-23T00:00:00) Singh, Yogesh; Sanjay, Kulkarni Swanand; Kumar, Pradeep; Singh, Satwinder; Thareja, SureshHypoxia-inducible factor (HIF) is a transcriptional factor which plays a crucial role in tumour metastasis thereby responsible for development of various forms of cancers. Indazole derivatives have been reported in the literature as potent HIF-1? inhibitor via interaction with key residues of the HIF-1? active site. Taking into consideration the role HIF-1? in cancer and potency of indazole derivative against HIF-1?; it was considered of interest to correlate structural features of known indazole derivatives with specified HIF-1? inhibitory activity to map pharmacophoric features through Three-dimensional quantitative structural activity relationship (3D-QSAR) and pharmacophore mapping. Field and Gaussian based 3D-QSAR studies were performed to realize the variables influencing the inhibitory potency of HIF-1? inhibitors. Field and Gaussian- based 3D-QSAR models were validated through various statistical measures generated by partial least square (PLS). The steric and electrostatic maps generated for both 3D-QSAR provide a structural framework for designing new inhibitors. Further; 3D-maps were also helpful in understanding variability in the activity of the compounds. Pharmacophore mapping also generates a common five-point pharmacophore hypothesis (A1D2R3R4R5_4) which can be employed in combination with 3D-contour maps to design potent HIF-1? inhibitors. Molecular docking and molecular dynamics (MD) simulation of the most potent compound 39 showed good binding efficiency and was found to be quite stable in the active site of the HIF-1? protein. The developed 3D-QSAR models; pharmacophore modelling; molecular docking studies along with the MD simulation analysis may be employed to design lead molecule as selective HIF-1? inhibitors for the treatment of Cancer. � 2022 Informa UK Limited, trading as Taylor & Francis Group.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.Item Role of peroxisome proliferator-activated receptor gamma (Ppar?) in different disease states: Recent updates(Bentham Science Publishers, 2020-07-17T00:00:00) Mal, Suvadeep; Dwivedi, Ashish Ranjan; Kumar, Vijay; Kumar, Naveen; Kumar, Bhupinder; Kumar, VinodPeroxisome proliferator-activated receptor (PPAR), a ligand dependant transcription factor, is a member of the nuclear receptor superfamily. PPAR exists in three isoforms i.e. PPAR alpha (PPAR?), PPAR beta (PPAR?), and PPAR gamma (PPAR?). These are multi-functional transcription factors and help in regulating inflammation, type 2 diabetes, lipid concentration in the body, metastasis, and tumor growth or angiogenesis. Activation of PPAR? causes inhibition of growth of cultured human breast, gastric, lung, prostate, and other cancer cells. PPAR? is mainly involved in fatty acid storage, glucose metabolism, and homeo-stasis and adipogenesis regulation. A large number of natural and synthetic ligands bind to PPAR? and modulate its activity. Ligands such as thiazolidinedione troglitazone, rosiglita-zone, pioglitazone effectively bind to PPAR?; however, most of these were found to display severe side effects such as hepatotoxicity, weight gain, cardiovascular complications and bladder tumor. Now the focus is shifted towards the development of dual-acting or pan PPAR ligands. The current review article describes the functions and role of PPAR? in various disease states. In addition, recently reported PPAR? ligands and pan PPAR ligands were dis-cussed in detail. It is envisaged that the present review article may help in the development of potent PPAR ligands with no or minimal side effects. � 2021 Bentham Science Publishers.