Pharmaceutical Sciences and Natural Products - Research Publications
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Item Polycystic ovary syndrome: Current scenario and future insights(Elsevier Ltd, 2023-11-05T00:00:00) Kulkarni, Swanand; Gupta, Khushi; Ratre, Pooja; Mishra, Pradyumna Kumar; Singh, Yogesh; Biharee, Avadh; Thareja, SureshPolycystic ovary syndrome (PCOS) prevails in approximately 33% of females of reproductive age globally. Although the root cause of the disease is unknown, attempts are made to clinically manage the disturbed hormone levels and symptoms arising due to hyperandrogenism, a hallmark of PCOS. This review presents detailed insights on the etiology, risk factors, current treatment strategies, and challenges therein. Medicinal agents currently in clinical trials and those in the development pipeline are emphasized. The significance of the inclusion of herbal supplements in PCOS and the benefits of improved lifestyle are also explained. Last, emerging therapeutic targets for treating PCOS are elaborated. The present review will assist the research fraternity working in the concerned domain to access significant knowledge associated with PCOS. � 2023 Elsevier LtdItem Oxazoline/amide derivatives against M. tuberculosis: experimental, biological and computational investigations(Taylor and Francis Ltd., 2023-11-10T00:00:00) Bajpai, Priyanka; Singh, Ankit Kumar; Kandagalla, Shivanada; Chandra, Phool; Kumar Sah, Vimlendu; Kumar, Pradeep; Grishina, Maria; Verma, Om Prakash; Pathak, PrateekTuberculosis (TB) is a treatable contagious disease that continuously kills approximately 2 million people yearly. Different oxazoline/amide derivatives were synthesized, and their anti-tuberculosis activity was performed against different strains of Mtb. This study designed the anti-Mtb compounds based on amide and oxazoline, two different structural moieties. The compounds were further synthesized and characterized by spectral techniques. Their anti-Tb activity was evaluated against strain (M. tuberculosis: H37Rv). Selectivity and binding affinity of all synthesized compounds (2a�2e, 3a�3e) against PanK in Mtb were investigated through molecular docking. Molecular dynamics simulation studies for the promising compounds 2d and 3e were performed for 100 ns. The stability of these complexes was assessed by calculating the root mean square deviation, solvent-accessible surface area, and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Among all synthesized compounds, 2d and 3e had comparable antitubercular activity against standard drug, validated by their computational and biological study. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Design and Fabrication of a Nanobiosensor for the Detection of Cell-Free Circulating miRNAS-LncRNAS-mRNAS Triad Grid(American Chemical Society, 2023-10-18T00:00:00) Ratre, Pooja; Nazeer, Nazim; Bhargava, Arpit; Thareja, Suresh; Tiwari, Rajnarayan; Raghuwanshi, Vinay Singh; Mishra, Pradyumna KumarThe increased understanding of the competitive endogenous RNA (ceRNA) network in the onset and development of breast cancers has suggested their use as promising disease biomarkers. Keeping these RNAs as molecular targets, we designed and developed an optical nanobiosensor for specific detection of the miRNAs-LncRNAs-mRNAs triad grid in circulation. The sensor was formulated using three quantum dots (QDs), i.e., QD-705, QD-525, and GQDs. These QDs were surface-activated and modified with a target-specific probe. The results suggested the significant ability of the developed nanobiosensor to identify target RNAs in both isolated and plasma samples. Apart from the higher specificity and applicability, the assessment of the detection limit showed that the sensor could detect the target up to 1 fg concentration. After appropriate validation, the developed nanobiosensor might prove beneficial to characterizing and detecting aberrant disease-specific cell-free circulating miRNAs-lncRNAs-mRNAs. � 2023 The Authors. Published by American Chemical Society.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 Medicinal Chemistry Aspects of Isoxazole Analogues as Anti-tubercular Agents(Bentham Science Publishers, 2023-10-11T00:00:00) Singh, Harshwardhan; Anila, Kumari V. S.; Singh, Ankit Kumar; Kumar, Adarsh; Kumar, PradeepTuberculosis (TB) is the major cause of mortality around the world and one of the most common diseases linked to AIDS. Due to the emergence of multi-drug resistance, extensive drug resistance, and total drug resistance strains, TB has become a difficult disease to treat. Isoxazole scaffold shows a wide range of biological activities, including anticancer, antibacterial, anti-tubercular, antiviral, and anti-inflammatory activities etc. Several isoxazole derivatives have been produced and few of them have shown comparable anti-tubercular activity with standard drugs. In this review, we have focused on reported isoxazole derivatives having anti-tubercular activity and summarized their structure-activity relationship. � 2023 Bentham Science Publishers.Item Design, one-pot synthesis, computational and biological evaluation of diaryl benzimidazole derivatives as MEK inhibitors(Taylor and Francis Ltd., 2023-10-09T00:00:00) Ram, Teja; Singh, Ankit Kumar; Pathak, Prateek; Kumar, Adarsh; Singh, Harshwardhan; Grishina, Maria; Novak, Jurica; Kumar, PradeepMEK mutations are more common in various human malignancies, such as pancreatic cancer (70�90%), mock melanoma (50%), liver cancer (20�40%), colorectal cancer (25�35%), melanoma (15�20%), non-small cell lung cancer (10�20%) and basal breast cancer (1�5%). Considering the significance of MEK mutations in diverse cancer types, the rational design of the proposed compounds relies on the structural resemblance to FDA-approved MEK inhibitors like selumetinib and binimetinib. The compound under design features distinct substitutions at the benzimidazole moiety, specifically at positions 2 and 3, akin to the FDA-approved drugs, albeit differing in positions 5 and 6. Subsequent structural refinement was guided by key elements including the DFG motif, hydrophobic pocket and catalytic loop of the MEK protein. A set of 15 diverse diaryl benzimidazole derivatives (S1�S15) were synthesized via a one-pot approach and characterized through spectroscopic techniques, including MASS, IR, 1H NMR and 13C NMR. In vitro anticancer activities of all the synthesized compounds were evaluated against four cancer cell lines, A375, HT ?29, A431 and HFF, along with the standard drug trametinib. Molecular docking was performed for all synthesized compounds (S1�15), followed by 950 ns molecular dynamics simulation studies for the promising compounds S1, S5 and S15. The stability of these complexes was assessed by calculating the root-mean-square deviation, solvent accessible surface area and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Based on the biological and computational results, S15 was the most potent compound and S1 and S5 are comparable to the standard drug trametinib. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Boron in cancer therapeutics: An overview(Elsevier Inc., 2023-10-17T00:00:00) Kulkarni, Swanand; Bhandary, Dyuti; Singh, Yogesh; Monga, Vikramdeep; Thareja, SureshBoron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1?, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies. � 2023 Elsevier Inc.Item Applications of dihydropyrimidinone derivatives on blood cancer and colon cancer(Elsevier, 2023-08-25T00:00:00) Singh, Ankit Kumar; Singh, Harshwardhan; Sonawane, Pankaj; Kumar, Adarsh; Verma, Amita; Kumar, PradeepDihydropyrimidinones (DHPMs) are characterized by their multifunctionalized scaffold with a pyrimidine moiety that exhibits diverse biological activities, especially anticancer activity. Malignant clonal expansion of blood-forming cells is referred to as blood cancer. Colorectal cancer (CRC) appears within the colon or another bodily area. There were 9,958,133 fatalities and 19,292,789 new cases of 36 cancers globally in 2020. In this, 1,148,515 cases and 576,858 deaths belong to colon cancer, whereas 474,519 cases and 311,594 deaths belong to leukemia. Different blood cancer cell lines, such as MOLT-4, HL-60, CCRF-CEMT, K-562, U937, MOLT-4, RPMI-8226, THP-1, and SR, as well as colon cancer/CRC cell lines, HCT-116, HCT-15, Colo205, HCC-2998, HCT-116, HT-29, KM-12, and SW-620, have been used to evaluate in vitro anticancer activity of DHPM derivatives. DHPM derivatives demonstrated notable effectiveness against blood and colon/colorectal cancers and may prove important building blocks in the development of novel anticancer agents. � 2023 Elsevier Inc. All rights reserved.Item Dihydropyrimidinone scaffold and potential therapeutic targets(Elsevier, 2023-08-25T00:00:00) Kumar, Adarsh; Singh, Ankit Kumar; Vijayan, Veena; Singh, Harshwardhan; Verma, Amita; Kumar, PradeepDihydropyrimidine is the most important heterocyclic ring system involved in the synthesis of RNA and DNA. Dihydropyrimidines were produced synthetically by multicomponent reactions such as the Biginelli reaction. Because of their remarkable biological characteristics, dihydropyrimidinones (DHPMs) have drawn considerable attention in recent years. In this chapter, we have described the synthetic and pharmacological properties of DHPMs employing multicomponent synthesis. It emphasizes also widespread pharmaceutical applications of DHPMs, including antitubercular, antifilarial, antihypertensive, antiinflammatory, anticancer, antifungal, antibacterial, anti-HIV, antihyperglycemic, anti-SARS, analgesic, antioxidant, anticonvulsant, anti-Alzheimer�s and antihepatitis properties. This chapter will be of immense importance for the scientists working in this area. � 2023 Elsevier Inc. All rights reserved.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.