School Of Basic And Applied Sciences
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Item Probing the molecular mechanisms of ?-synuclein inhibitors unveils promising natural candidates through machine-learning QSAR, pharmacophore modeling, and molecular dynamics simulations(Institute for Ionics, 2023-07-18T00:00:00) Boulaamane, Yassir; Jangid, Kailash; Britel, Mohammed Reda; Maurady, AmalParkinson�s disease is characterized by a multifactorial nature that is linked to different pathways. Among them, the abnormal deposition and accumulation of ?-synuclein fibrils is considered a neuropathological hallmark of Parkinson�s disease. Several synthetic and natural compounds have been tested for their potency to inhibit the aggregation of ?-synuclein. However, the molecular mechanisms responsible for the potency of these drugs to further rationalize their development and optimization are yet to be determined. To enhance our understanding of the structural requirements necessary for modulating the aggregation of ?-synuclein fibrils, we retrieved a large dataset of ?-synuclein inhibitors with their reported potency from the ChEMBL database to explore their chemical space and to generate QSAR models for predicting new bioactive compounds. The best performing QSAR model was applied to the LOTUS natural products database to screen for potential ?-synuclein inhibitors followed by a pharmacophore design using the representative compounds sampled from each cluster in the ChEMBL dataset. Five natural products were retained after molecular docking studies displaying a binding affinity of ? 6.0�kcal/mol or lower. ADMET analysis revealed satisfactory properties and predicted that all the compounds can cross the blood�brain barrier and reach their target. Finally, molecular dynamics simulations demonstrated the superior stability of LTS0078917 compared to the clinical candidate, Anle138b. We found that LTS0078917 shows promise in stabilizing the ?-synuclein monomer by specifically binding to its hairpin-like coil within the N-terminal region. Our dynamic analysis of the inhibitor-monomer complex revealed a tendency towards a more compact conformation, potentially reducing the likelihood of adopting an elongated structure that favors the formation and aggregation of pathological oligomers. These findings offer valuable insights for the development of novel ?-synuclein inhibitors derived from natural sources. Graphical abstract: [Figure not available: see fulltext.]. � 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.Item A review on reported phytochemicals as druggable leads with antimalarial potential(Springer, 2023-07-04T00:00:00) Guchait, Avishek; Kumar, Asim; Singh, Roopam; Joshi, Gaurav; Dwivedi, Ashish RanjanThe science and practice of drug discovery and development is primarily benefitted from the natural sources. The chemistry of natural products has inspired medicinal chemists to develop and design various therapeutic molecules from the leads obtained from natural sources. This is evident from the growing number of publications on natural products derived from drug molecules. Some of the most successful bioactive natural product candidates so far are Taxol obtained from �Taxus Brevifolia,� Quinine obtained from the bark of the cinchona plant, morphine obtained from the dried latex of the poppy plant, Vincristine, and Vinblastine from �Vinca Rosea,� atropine from �Atropa Belladonna�, Digoxin and Digitoxin from �Digitalis Purpurea� and Artemisinin from �Artemisia Annua�. Parasitic pathogens are one of the significant menaces for the world as they lead to various diseases in hosts, and for many diseases, these parasite compromises the host�s immune system. Malaria is a parasitic disease especially endemic to tropical countries and is one of the leading causes of death worldwide. According to the latest data from WHO, millions of patients are suffering from malaria and its related complications on 30th March 2022. Natural products derived leads have brought a paradigm shift in the discovery of antimalarial drugs. The first antimalarial drug, quinine, was isolated from the Cinchona species (Family: Rubiaceae) in 1820 and is still used today. This was followed by another antimalarial drug a century later, chloroquine, discovered in the 1940s. After that, Artemisinin was founded in 1972 by Tu Youyou, co-recipient of the 2015 Nobel Prize in Medicine for her discovery. Unfortunately, the malarial parasite, mainly Plasmodium falciparum, develops resistance to these drugs, and thus there exists a need to explore other natural herbs for their role as antimalarials. The current review is therefore kept forth to congregate updated information on undergoing research in allied areas of natural product-based drug discovery, particularly for developing antimalarial agents. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Recent efforts for drug identification from phytochemicals against SARS-CoV-2: Exploration of the chemical space to identify druggable leads(Elsevier Ltd, 2021-04-03T00:00:00) Joshi, Gaurav; Sindhu, Jayant; Thakur, Shikha; Rana, Abhilash; Sharma, Geetika; Mayank; Poduri, RamaraoNature, which remains a central drug discovery pool, is always looked upon to find a putative druggable lead. The natural products and phytochemical derived from plants are essential during a global health crisis. This class represents one of the most practical and promising approaches to decrease pandemic's intensity owing to their therapeutic potential. The present manuscript is therefore kept forth to give the researchers updated information on undergoing research in allied areas of natural product-based drug discovery, particularly for Covid-19 disease. The study briefly shreds evidence from in vitro and in silico researches done so far to find a lead molecule against Covid-19. Following this, we exhaustively explored the concept of chemical space and molecular similarity parameters for the drug discovery about the lead(s) generated from in silico-based studies. The comparison was drawn using FDA-approved anti-infective agents during 2015�2020 using key descriptors to evaluate druglike properties. The outcomes of results were further corroborated using Molecular Dynamics studies which suggested the outcomes in alignment with chemical space ranking. In a nutshell, current research work aims to provide a holistic strategic approach to drug design, keeping in view the identified phytochemicals against Covid-19. � 2021 Elsevier LtdItem Historical Perspective of Drug Discovery and Development(Springer Singapore, 2021-02-18T00:00:00) Poduri, RamaraoHistorically ever since the existence of humans on this planet the process of drug discovery was started by trial and error method. Initially they tested the natural products on self to understand the effects. Serendipity played a great role in the evolution of drug discovery. Isolation of active ingredients from plants started in the early nineteenth century. The advances in the field of chemical and biological sciences started the modern drug discovery and development. The regulatory processes became stringent due to some adverse events in the second half of the twentieth century. Currently the digital and disruptive technologies are changing the scenario of drug discovery and development and producing efficacious and safe drugs. � Springer Nature Singapore Pte Ltd. 2021.Item Exploring the magic bullets to identify Achilles� heel in SARS-CoV-2: Delving deeper into the sea of possible therapeutic options in Covid-19 disease: An update(Elsevier Ltd, 2020-11-27T00:00:00) Thakur, Shikha; Mayank; Sarkar, Bibekananda; Ansari, Arshad J.; Khandelwal, Akanksha; Arya, Anil; Poduri, Ramarao; Joshi, GauravThe symptoms associated with Covid-19 caused by SARS-CoV-2 in severe conditions can cause multiple organ failure and fatality via a plethora of mechanisms, and it is essential to discover the efficacious and safe drug. For this, a successful strategy is to inhibit in different stages of the SARS-CoV-2 life cycle and host cell reactions. The current review briefly put forth the summary of the SARS-CoV-2 pandemic and highlight the critical areas of understanding in genomics, proteomics, medicinal chemistry, and natural products derived drug discovery. The review further extends to briefly put forth the updates in the drug testing system, biologics, biophysics, and their advances concerning SARS-CoV-2. The salient features include information on SARS-CoV-2 morphology, genomic characterization, and pathophysiology along with important protein targets and how they influence the drug design and development against SARS-CoV-2 and a concerted and integrated approach to target these stages. The review also gives the status of drug design and discovery to identify the drugs acting on critical targets in SARS-CoV-2 and host reactions to treat Covid-19. � 2020 Elsevier LtdItem Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity(Springer Science and Business Media Deutschland GmbH, 2023-09-04T00:00:00) Rana, Harvesh Kumar; Singh, Amit Kumar; Kumar, Ramesh; Pandey, Abhay K.Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium which causes tuberculosis (TB). TB control programmes are facing threats from drug resistance. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains need longer and more expensive treatment with many medications resulting in more adverse effects and decreased chances of treatment outcomes. The World Health Organization (WHO) has emphasised the development of not just new individual anti-TB drugs, but also novel medication regimens as an alternative treatment option for the drug-resistant Mtb strains. Many plants, as well as marine creatures (sponge; Haliclona sp.) and fungi, have been continuously used to treat TB in various traditional treatment systems around the world, providing an almost limitless supply of active components. Natural products, in addition to their anti-mycobacterial action, can be used as adjuvant therapy to increase the efficacy of conventional anti-mycobacterial medications, reduce their side effects, and reverse MDR Mtb strain due to Mycobacterium�s genetic flexibility and environmental adaptation. Several natural compounds such as quercetin, ursolic acid, berberine, thymoquinone, curcumin, phloretin, and propolis have shown potential anti-mycobacterial efficacy and are still being explored in preclinical and clinical investigations for confirmation of their efficacy and safety as anti-TB medication. However, more high-level randomized clinical trials are desperately required. The current review provides an overview of drug-resistant TB along with the latest anti-TB medications, drug-induced hepatotoxicity and oxidative stress. Further, the role and mechanisms of action of first and second-line anti-TB drugs and new drugs have been highlighted. Finally, the role of natural compounds as anti-TB medication and hepatoprotectants�have been described and their mechanisms discussed. � 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Item Current therapeutic modalities and chemopreventive role of natural products in liver cancer: Progress and promise(Baishideng Publishing Group Inc, 2023-01-15T00:00:00) Singh, Amit Kumar; Singh, Shiv Vardan; Kumar, Ramesh; Kumar, Shashank; Senapati, Sabyasachi; Pandey, Abhay KLiver cancer is a severe concern for public health officials since the clinical cases are increasing each year, with an estimated 5-year survival rate of 30%�35% after diagnosis. Hepatocellular carcinoma (HCC) constitutes a significant subtype of liver cancer (approximate75%) and is considered primary liver cancer. Treatment for liver cancer mainly depends on the stage of its progression, where surgery including, hepatectomy and liver transplantation, and ablation and radiotherapy are the prime choice. For advanced liver cancer, various drugs and immunotherapy are used as first-line treatment, whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins. Sorafenib and lenvatinib are first-line therapies, while regorafenib and ramucirumab are secondline therapy. Various metabolic and signaling pathways such as Notch, JAK/ STAT, Hippo, TGF-?, and Wnt have played a critical role during HCC progression. Dysbiosis has also been implicated in liver cancer. Drug-induced toxicity is a key obstacle in the treatment of liver cancer, necessitating the development of effective and safe medications, with natural compounds such as resveratrol, curcumin, diallyl sulfide, and others emerging as promising anticancer agents. This review highlights the current status of liver cancer research, signaling pathways, therapeutic targets, current treatment strategies and the chemopreventive role of various natural products in managing liver cancer � The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reservedItem P53-mediated anticancer activity of Citrullus colocynthis extracts(Bentham Science Publishers, 2019) Joshi G.; Kaur J.; Sharma P.; Kaur G.; Bhandari Y.; Kumar R.; Singh S.Background: Current anticancer therapeutics comes with significant side effects and thus focus is shifting towards minimizing the side effects or to avoid the disease altogether. Thus, various natural products are being investigated for their potential therapeutic values which can be easily included in daily diet of a person. Citrullus colocynthis (L.) fruit is commonly used in traditional medicines and is known to have antioxidant effects, thus may possess potent anticancer activity as well. Objectives: To establish the anticancer potential of fruit belonging to Citrullus colocynthis (L.) and delineate the potential targets. Results: In the present study it was found that seed and pulp extracts of the fruit are effective against various cancer cell lines while the normal cells, with lower rate of division, remain largely unaffected. The current study for the first time shows that these extracts function via regulation of p53 pathways and the mode of apoptosis is mostly via mitochondrial (intrinsic) pathway. The biological profiling of the extracts was also validated using molecular modelling studies utilizing the two major polyphenols constituents from colocynths i.e., Isoorientin and Isovitexin. Conclusion: The study suggested that the constituent has a multiple target approach for the inhibition of cancer cell proliferation and inhibition of ROS production via the major apoptotic proteins. All of these outcomes suggest and establish a critical role of ROS accumulation and mitochondrial function in the p53-dependent cell.Item Bulbine frutescens phytochemical inhibits notch signaling pathway and induces apoptosis in triple negative and luminal breast cancer cells(Elsevier Inc., 2019) Kushwaha P.P.; Vardhan P.S.; Kapewangolo P.; Shuaib M.; Prajapati S.K.; Singh A.K.; Kumar S.Breast cancer (BCa) is the most commonly diagnosed lethal cancer in women worldwide. Notch signaling pathway is directly linked to BCa recurrence and aggressiveness. Natural remedies are becoming a prime choice to overcome against cancer due to lesser side effect and cost-effectiveness. Bulbine frutescens (Asphodelaceae), a traditional medicinal plant in South Africa possess bioactive flavonoids and terpenoids. Polar (methanol) and non-polar (hexane) B. frutescens plant extracts were prepared. GC–MS analysis revealed the differential presence of secondary metabolites in both methanolic and hexane extracts. We hereby first time evaluated the anticancer potential of B. frutescens methanolic and hexane extract in triple-negative and luminal BCa cells. B. frutescens extracts significantly decreased cell viability (IC50 4.8–28.4 μg/ml) and induced cell cycle arrest at G1 phase in MDA-MB-231 and T47D cells as confirmed by spectrophotometry and flow cytometry technique. RT-PCR analysis of cell cycle (cyclin D1, CDK4, and p21) and apoptosis modulating genes (caspase 3, Bcl2 and survivin) revealed upexpression of p21, and caspase 3, and down expression of cyclin D1, CDK4, Bcl2 and survivin genes in extract-treated BCa cells. Fluorescence spectrophotometry and confocal microscopy showed B. frutescens induced nuclear morphology and mitochondrial integrity disruption, and increased reactive oxygen species production in MDA-MB-231 and T47D cells. Flow cytometric apoptosis analysis of B. frutescens extracts treated MDA-MB-231 cells showed ≈13% increase in early apoptotic population in comparison to non-treated cells. Dual-Luciferase Reporter assay confirmed notch promoter inhibitory activity of B. frutescens extracts. Moreover, RTPCR analysis showed down regulation of notch responsive genes (Hes1 and Hey1) at transcription levels in extract-treated BCa cells. Western Blot analysis showed increased procaspase 3 protein expression in extract-treated BCa cells. In all the assays methanolic extract showed better anti-cancer properties. Literature-based identification of methanol soluble phytochemicals in B. frutescens and in silico docking study revealed Bulbineloneside D as a potent ϒ-secretase enzyme inhibitor. In comparison to standard notch inhibitor, lead phytochemical showed two additional hydrophobic interactions with Ala80 and Leu81 amino acids. In conclusion, B. frutescens phytochemicals have cell cycle arrest, ROS production, apoptosis induction, and mitochondria membrane potential disruption efficacy in breast cancer cells. B. frutescens phytochemicals have the ability to downregulate the notch signaling pathway in triple-negative and luminal breast cancer cells.Item Natural products as multidrug resistance modulators in cancer(Elsevier, 2019) Kumar, Amit; Jaitak, VikasCancer is a prominent cause of death globally. Currently, many drugs that are in clinical practice are having a high prevalence of side effect and multidrug resistance. Risk of tumors acquiring resistance to chemotherapy (multidrug resistance) remains a significant hurdle to the successful treatment of various types of cancer. Membrane-embedded drug transporters, generally overexpressed in cancer, are the leading cause among multiple mechanisms of multidrug resistance (MDR). P-glycoprotein (P-gp) also MDR1/ABCB1, multidrug resistance associated protein 1 (MRP1/ABCC1), MRP2 and breast cancer resistance protein (BCRP/ABCG2) are considered to be a prime factor for induction of MDR. To date, several chemical substances have been tested in a number of clinical trials for their MDR modulatory activity which are not having devoid of any side effects that necessitates to find newer and safer way to tackle the current problem of multidrug resistance in cancer. The present study systematically discusses the various classes of natural products i.e flavonoids, alkaloids, terpenoids, coumarins (from plants, marine, and microorganisms) as potential MDR modulators and/or as a source of promising lead compounds. Recently a bisbenzyl isoquinoline alkaloid namely tetrandrine, isolated from Chinese herb Stephania tetrandra (Han-Fang-Chi) is in clinical trials for its MDR reversal activity. © 2019 Elsevier Masson SAS