Department Of Pharmaceutical Sciences and Natural Products
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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 Identification of terpenoids as dihydropteroate synthase and dihydrofolate reductase inhibitors through structure-based virtual screening and molecular dynamic simulations(Taylor and Francis Ltd., 2023-05-13T00:00:00) Saini, Abhishek; Kumar, Amit; Jangid, Kailash; Kumar, Vinod; Jaitak, VikasBacterial infections are rising, and antimicrobial resistance (AMR) in bacteria has worsened the scenario, requiring extensive research to find alternative therapeutic agents. Terpenoids play an essential role in protecting plants from herbivores and pathogens. The present study was designed to focus on in silico evaluation of terpenoids for their affinity towards two necessary enzymes, i.e. DHFR and DHPS, which are involved in forming 5, 6, 7, 8-tetrahydrofolate, a key component in bacterial DNA synthesis proteins. Additionally, to account for activity against resistant bacteria, their affinity towards the L28R mutant of DHFR was also assessed in the study. The structure-based drug design approach was used to screen the compound library of terpenes for their interaction with active sites of DHFR and DHPS. Further, compounds were screened based on their dock score, pharmacokinetic properties, and binding affinities. A total of five compounds for each target protein were screened, having dock scores better than their respective standard drug molecules. CNP0169378 (?8.4 kcal/mol) and CNP0309455 (?6.5 kcal/mol) have been identified as molecules with a higher affinity toward the targets of DHFR and DHPS, respectively. At the same time, one molecule CNP0298407 (?5.8 kcal/mol for DHPS, ?7.6 kcal/mol for DHFR, ?6.1 kcal/mol for the L28R variant), has affinity for both proteins (6XG5 and 6XG4). All the molecules have good pharmacokinetic properties. We further validated the docking study by binding free energy calculations using the MM/GBSA approach and molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Structure-based Virtual Screening and Molecular Dynamic Simulation Approach for the Identification of Terpenoids as Potential DPP-4 Inhibitors(Bentham Science Publishers, 2023-05-16T00:00:00) Pulikkottil, Ajay Aravind; Kumar, Amit; Jangid, Kailash; Kumar, Vinod; Jaitak, VikasBackground: Diabetes mellitus is a metabolic disorder where insulin secretion is compromised, leading to hyperglycemia. DPP-4 is a viable and safer target for type 2 diabetes mellitus. Computational tools have proven to be an asset in the process of drug discovery. Objective: In the present study, tools like structure-based virtual screening, MM/GBSA, and pharmacokinetic parameters were used to identify natural terpenoids as potential DPP-4 inhibitors for treating diabetes mellitus. Methods: Structure-based virtual screening, a cumulative mode of elimination technique, was adopted, identifying the top five potent hit compounds depending on the docking score and nonbonding interactions. Results: According to the docking data, the most important contributors to complex stability are hydrogen bonding, hydrophobic interactions, and Pi-Pi stacking interactions. The dock scores ranged from-6.492 to-5.484 kcal/mol, indicating robust ligand-protein interactions. The pharmacokinetic characteristics of top-scoring hits (CNP0309455, CNP0196061, CNP0122006, CNP0 221869, CNP0297378) were also computed in this study, confirming their safe administration in the human body. Also, based on the synthetic accessibility score, all top-scored hits are easily synthesizable. Compound CNP0309455 was quite stable during molecular dynamic simulation studies. Conclusion: Virtual database screening yielded new leads for developing DPP-4 inhibitors. As a result, the findings of this study can be used to design and develop natural terpenoids as DPP-4 inhibitors for the medication of diabetes mellitus. � 2024 Bentham Science Publishers.Item Synthesis and in-silico Studies of 4-phenyl Thiazol-2-amine Derivatives as Putative Anti-breast Cancer Agents(Bentham Science Publishers, 2023-03-22T00:00:00) Lavanya, Kanamarlapudi Joshna; Kaur, Kamalpreet; Jaitak, VikasBackground: Breast cancer (BC) is the second-leading cause of cancer-related fatalities in women after lung cancer worldwide. The development of BC is significantly influenced by estrogen receptors (ERs). The problem with current cancer treatments is selectivity, target specificity, cytotoxicity, and developing resistance. Thiazole scaffolds are gaining popularity in drug discovery due to their broad range of biological activity. It has the extraordinary capacity to control a variety of cellular pathways, and its potential for selective anticancer activity can be explored. Objective: Synthesis and in-silico studies of 4-Phenyl thiazol-2-amine derivatives as anti-breast cancer agents and molecular docking was used to assess the compounds� capacity to bind ER-? protein target. Methods: In this study, 4-Phenylthiazol-2-amine derivatives (3a-j) have been synthesized, and using Schrodinger software, molecular docking and ADME studies of the compounds were conducted. Results: Most of the synthesized compounds have shown dock scores ranging from-6.658 to 8.911 kcal/mol, which is better than the standard drug tamoxifen (-6.821 kcal/mol). According to molecular docking, all compounds fit in the protein�s active site and have the same hydrophobic pocket as the standard drug tamoxifen. Further, all of the compounds� ADME properties are below acceptable limits. Conclusion: Compound 3e showed the best docking score of-8.911. All compounds� ADME properties are within acceptable limits, and their p/o coefficients fall within a range, suggesting they will all have sufficient absorption at the site of action. These compounds can be evaluated invitro and in-vivo in the future. � 2024 Bentham Science Publishers.Item Sodium Dodecyl Sulphate Catalyzed One-Pot Three-Component Synthesis of Structurally Diverse 2-Amino-3-cyano Substituted Tetrahydrobenzo[b]pyrans and Spiropyrans in Water at Room Temperature(Springer, 2023-01-16T00:00:00) Banerjee, Bubun; Priya, Anu; Kaur, Manmeet; Sharma, Aditi; Singh, Arvind; Gupta, Vivek Kumar; Jaitak, VikasA facile and convenient method has been developed for the one-pot three-component synthesis of 2-amino-3-cyano substituted tetrahydrobenzo[b]pyran derivatives from the reactions of aromatic aldehydes, malononitrile and dimedone or 1,3-cyclohexanedione in the presence of a catalytic amount of sodium dodecyl sulphate as an efficient surfactant type catalyst in water at room temperature. Synthesis of 2-amino-3-cyano substituted spiropyrans was also achieved under the same reaction conditions starting from ninhydrin/isatins, malononitrile and dimedone or 1,3-cyclohexanedione. All the reactions were completed within 2.5�h and the desired products afforded in good to excellent yields. Gram scale production of the desired compound was also achieved. Use of water as green solvent, commercially available low cost surfactant type catalyst, high atom economy, excellent yields, energy efficiency, no column chromatographic purifications, reusability of the solvent media, multiple carbon�carbon and carbon-heteroatom bond formations are some of the major advantages of this newly developed protocol. Graphical Abstract: [Figure not available: see fulltext.] � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Glycine Catalyzed One-Pot Three-Component Synthesis of Structurally Diverse 2-Amino Substituted Pyran Annulated Heterocycles in Aqueous Ethanol under Refluxed Conditions(Bentham Science Publishers, 2022-12-14T00:00:00) Banerjee, Bubun; Kaur, Manmeet; Sharma, Aditi; Singh, Arvind; Priya, Anu; Gupta, Vivek Kumar; Jaitak, VikasIntroduction: A facile, convenient and general method has been developed for the one-pot three-component synthesis of structurally diverse 2-amino pyran annulated heterocycles from the reactions of aromatic aldehydes, malononitrile and various C-H activated acids in the presence of a catalytic amount of glycine as an efficient metal-free organocatalyst in aqueous ethanol under refluxed conditions. Methods: Using this developed protocol, we were able to synthesize a series of structurally diverse 2-amino pyran derivatives viz., 2-amino-4,5-dihydropyrano[3,2-c]chromenes, 2-amino-4,5-dihydropyrano [4,3-b]pyrans, 2-amino-5,6,7,8-tetrahydro-4H-chromenes, 2'-amino-2,5'-dioxo-5'H-spiro[indoline-3,4'-pyrano [3,2-c]chromene]-3'-carbonitrile and 2'-amino-1,3,5'-trioxo-1,3-dihydro-5'H-spiro[indene-2,4'-pyrano[3,2-c]chromene]-3'-carbonitrile in excellent yields. Result: Synthesis of biologically promising pyrans and spiropyrans, high atom economy, excellent yields, use of metal-free catalyst, less toxic solvents, no chromatographic column purifications, multiple carbon-carbon and carbon-heteroatom bond formations are some of the major advantages of this newly developed protocol. Conclusion: In conclusion, we have developed a simple, convenient, and efficient method for the synthesis of a series of structurally diverse 2-amino pyran annulated heterocyclic derivatives. � 2022 Bentham Science Publishers.Item Mandelic acid catalyzed one-pot pseudo three-component synthesis of various trisubstituted methane derivatives at room temperature(Arkat, 2022-11-03T00:00:00) Banerjee, Bubun; Singh, Arvind; Sharma, Aditi; Priya, Anu; Kaur, Manmeet; Kaur, Gurpreet; Gupta, Vivek Kumar; Jaitak, VikasA simple, mild, eco-friendly, general and convenient approach has been developed for the synthesis of various trisubstituted methane derivatives via one-pot pseudo three-component reactions between one equivalent of aromatic aldehydes and two equivalents of 6-amino-uracils or dimedone respectively using a catalytic amount of mandelic acid as a low cost, commercially available, efficient organo-catalyst in aqueous ethanol at room temperature. � 2022 Arkat. All rights reserved.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 Effectiveness of Selective Estrogen Receptor Modulators in Breast Cancer Therapy: An Update(Bentham Science Publishers, 2022-10-06T00:00:00) Das, Agnidipta; Lavanya, Kanamarlapudi Joshna; Nandini; Kaur, Kamalpreet; Jaitak, VikasBackground: Breast cancer is considered to be 2nd most common cancer sub-type investigated worldwide. It is mainly prevalent in postmenopausal women. Estrogen Receptor (ER) is a primary transcription factor for the survival and growth of tumors. Around 80% BCs of all classes are ER-positive (ER+). Powerful evidence for estrogen proved to be involved in BC pathogenesis both exogenously and endogenously. It brings the concept of ER inhibitors to treat BC with distinct mechanisms into focus and ER PROTACs (Proteolysis-Targeting Chimeras), AIs (Aromatase inhibitors), SERMs (Selec-tive estrogen receptor modulators), and SERDs (Selective estrogen receptor degrader) were developed. For over 30 years, Tamoxifen, a triphenylethylene SERM, was the drug of choice solely to treat ER+BC patients. Although several SERMs got approval by US FDA after tamoxifen, complicacies remain because of dangerous adverse effects like en-dometrial carcinoma, hot flashes, and VTE (Venous thromboembolism). In addition to that, drug-resistant tumors put a surging need for novel, potent candidates with no or low adverse effects for ER+ BC prevention. Objectives: This article explores the possibilities of SERMs as effective BC agents. Methods: A detailed literature survey of the history and recent advancements of SERMs has been carried out, taking BC as the primary target. This review provides information about ER structure, signaling, pharmacological action, chemical classification with SAR analysis, and benefits and adverse effects of SERMs as potential BC agents. Results: Exhaustive literature studies suggested that SERMs having an agonistic, antago-nistic or mixed activity to ER could efficiently inhibit BC cell proliferation. Conclusion: Each chemical class of SERMs comprises some salient features and poten-tials, which may be further investigated to obtain novel effective SERMs in BC therapy. � 2023 Bentham Science Publishers.Item Trisodium citrate dihydrate catalyzed one-pot pseudo four-component synthesis of fully functionalized pyridine derivatives(Taylor and Francis Ltd., 2022-07-22T00:00:00) Sharma, Aditi; Singh, Arvind; Priya, Anu; Kaur, Manmeet; Gupta, Vivek Kumar; Jaitak, Vikas; Banerjee, BubunA facile and convenient method has been developed for the one-pot pseudo-four component synthesis of fully functionalized pyridine derivatives from the reactions of aromatic aldehydes, malononitrile and thiols in the presence of a catalytic amount of trisodium citrate dihydrate as an efficient metal-free catalyst in aqueous ethanol under refluxed conditions. All the reactions were completed within just 45 minutes and the desired products afforded in excellent yields (90�95%). Gram scale production of the desired compound was also achieved. Synthesis of biologically promising scaffolds, high atom economy, excellent yields, use of metal-free catalyst, less toxic solvents, no column chromatographic purifications, reusability of the solvent media, multiple carbon-carbon and carbon-heteroatom bond formations are some of the major advantages of this newly developed protocol. � 2022 Taylor & Francis Group, LLC.
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