Browsing by Author "Mayank"
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Item Drug target strategies in breast cancer treatment: Recent developments(Bentham Science Publishers B.V., 2014) Mayank; Jaitak, Vikas; Mayank, Jaitak, V.Breast cancer (BC) is the leading cause of death among women all over the world. Estrogen receptor (ER) based therapy is one of the major approaches to target BC and is associated with various problems such as primary as well as secondary resistance. ER signaling is a complex pathway as many factors are involved; including several types of ERs and their associated co-regulators. Increasing understanding of ER signals results in new approaches targeting towards BCs. In this context, ER co-regulators have been explored and many modulators of ER co-regulators have been found out. EGFR and mTOR pathways also have significant impact on BC endocrine therapy because of the complex crosstalk mechanism which is responsible for primary and secondary resistance. Triple negative breast cancer (TNBC) is majorly associated with BRCA mutations. Currently there is no approved targeted therapy available in such form of cancer. Although PARP inhibitors seem to be suitable candidates for it. The present review is focused on the current scenario of ER, EGFR, as well as mTOR signaling target therapy. We have also discussed the current status of PARP inhibitors in BC chemotherapy. ? 2014 Bentham Science Publishers.Item Drug Targeting Strategies in Breast Cancer Treatment(Bentham Science, 2014) Mayank; Jaitak, VikasBreast cancer (BC) is the leading cause of death among women all over the world. Estrogen receptor (ER) based therapy is one of the major approaches to target BC and is associated with various problems such as primary as well as secondary resistance. ER signaling is a complex pathway as many factors are involved; including several types of ERs and their associated co-regulators. Increasing understanding of ER signals results in new approaches targeting towards BCs. In this context, ER co-regulators have been explored and many modulators of ER co-regulators have been found out. EGFR and mTOR pathways also have significant impact on BC endocrine therapy because of the complex crosstalk mechanism which is responsible for primary and secondary resistance. Triple negative breast cancer (TNBC) is majorly associated with BRCA mutations. Currently there is no approved targeted therapy available in such form of cancer. Although PARP inhibitors seem to be suitable candidates for it. The present review is focused on the current scenario of ER, EGFR, as well as mTOR signaling target therapy. We have also discussed the current status of PARP inhibitors in BC chemotherapy.Item Electro-organic synthesis of C-5 sulfenylated amino uracils: Optimization and exploring topoisomerase-I based anti-cancer profile(Academic Press Inc., 2023-06-10T00:00:00) Rani, Payal; Chahal, Sandhya; Kumar, Roshan; Mayank; Kumar, Parvin; Negi, Arvind; Singh, Rajvir; Kumar, Sudhir; Kataria, Ramesh; Joshi, Gaurav; Sindhu, JayantCancer is spreading worldwide and is one of the leading causes of death. The use of existing chemotherapeutic agents is frequently limited due to side effects. As a result, it is critical to investigate new agents for cancer treatment. In this context, we developed an electrochemical method for the synthesis of a series of thiol-linked pyrimidine derivatives (3a-3p) and explored their anti-cancer potential. The biological profile of the synthesized compounds was evaluated against breast (MDAMB-231 and MCF-7) and colorectal (HCT-116) cancer cell lines. 3b and 3d emerged to be the most potent agents, with IC50 values ranging between 0.98 to 2.45 �M. Target delineation studies followed by secondary anticancer parameters were evaluated for most potent compounds, 3b and 3d. The analysis revealed compounds possess DNA intercalation potential and selective inhibition towards human topoisomerase (hTopo1). The analysis was further corroborated by DNA binding studies and in silico-based molecular modeling studies that validated the intercalating binding mode between the compounds and the DNA. � 2023 Elsevier Inc.Item Exploring insights of hydroxychloroquine, a controversial drug in Covid-19: An update(Elsevier Ltd, 2021-03-18T00:00:00) Joshi, Gaurav; Thakur, Shikha; Mayank; Poduri, RamaraoThe review summarizes chloroquine (CQ) and its safer derivative hydroxychloroquine (HCQ) and its utility in Covid-19. Recently this well-established drug made its way back to the headlines during the SARS-CoV-2 pandemic. This led to an upsurge in the scientific arena with multiple research and review articles along with expert opinions and commentaries. The HCQ has received mixed judgements so far about its efficacy to be used in Covid-19 patients in a limited trial conducted all across the Globe. The purpose of our article is to put forth the history, pharmacodynamics, and pharmacokinetics, along with the existing studies favouring and disapproving the role of HCQ in the treatment of Covid-19. We grouped HCQ use at three stages, this includes HCQ for i. prophylactic use by asymptomatic health workers or peoples at higher risk; ii. patients having mild symptoms; iii. patients with extreme symptoms. The review critically discusses the underlying plausible reasons and mechanisms exploring HCQ in prophylactic management or treatment of SARS-CoV-2. Furthermore, we have critically analysed the reported pharmacokinetic parameters and compiled the proponent, opponent, or neutral opinions on the use of HCQ in Covid-19. Authors discretion is to conduct more studies considering the optimal dosing regimen and pharmacokinetics assessment. � 2021 Elsevier LtdItem Exploring the COVID-19 vaccine candidates against SARS-CoV-2 and its variants: where do we stand and where do we go?(Taylor and Francis Ltd., 2021-12-03T00:00:00) Joshi, Gaurav; Borah, Pobitra; Thakur, Shweta; Sharma, Praveen; Mayank; Poduri, RamaraoAs of September 2021, 117 COVID-19 vaccines are in clinical development, and 194 are in preclinical development as per the World Health Organization (WHO) published draft landscape. Among the 117 vaccines undergoing clinical trials, the major platforms include protein subunit; RNA; inactivated virus; viral vector, among others. So far, USFDA recognized to approve the Pfizer-BioNTech (Comirnaty) COVID-19 vaccine for its full use in individuals of 16�years of age and older. Though the approved vaccines are being manufactured at a tremendous pace, the wealthiest countries have about 28% of total vaccines despite possessing only 10.8% of the total world population, suggesting an inequity of vaccine distribution. The review comprehensively summarizes the history of vaccines, mainly focusing on vaccines for SARS-CoV-2. The review also connects relevant topics, including measurement of vaccines efficacy against SARS-CoV-2 and its variants, associated challenges, and limitations, as hurdles in global vaccination are also kept forth. � 2021 Taylor & Francis Group, LLC.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 Indole derivatives as anticancer agents for breast cancer therapy: A review(Bentham Science Publishers B.V., 2016) Sidhu, Jagpreet Singh; Singla, Ramit; Mayank; Jaitak, VikasBreast cancer (BC) is the second most common cause of cancer-related deaths in women throughout the world. Multiple drugs have been approved by US-FDA for breast related malignancies. Frequent emergence of resistances creates the severe need of newer moieties that are free from such problems. Drugs targeting breast cancer have been observed to be based on the multiple mechanisms of action, and various indole based anticancer agents have also been explored. Moreover, indoles have promising anti-cancer potential; there has been the emphasis on the synthesis of indole derivatives to overcome problems faced by existing therapeutic agents. Taking into consideration the above-mentioned facts we have analyzed in detail the possible role of indole based anticancer agents typically for breast related malignancies. This is the first exhaustive review that jointly covers various synthetic anticancer indole derivatives and related signaling pathways by which these derivatives have shown promising anti-breast cancer potential. ? 2016 Bentham Science Publishers.Item Interaction model of steviol glycosides from Stevia rebaudiana (Bertoni) with sweet taste receptors: A computational approach(Elsevier Ltd, 2015) Mayank; Jaitak, Vikas; Mayank, Jaitak, V.Docking studies were performed on natural sweeteners from Stevia rebaudiana by constructing homology models of T1R2 and T1R3 subunits of human sweet taste receptors. Ramachandran plot, PROCHECK results and ERRAT overall quality factor were used to validate the quality of models. Furthermore, docking results of steviol glycosides (SG's) were correlated significantly with data available in the literature which enabled to predict the exact sweetness rank order of SG's. The binding pattern indicated that Asn 44, Ans 52, Ala 345, Pro 343, Ile 352, Gly 346, Gly 47, Ala 354, Ser 336, Thr 326 and Ser 329 are the main interacting amino acid residues in case of T1R2 and Arg 56, Glu 105, Asp 215, Asp 216, Glu 148, Asp 258, Lys 255, Ser 104, Glu 217, Leu 51, Arg 52 for T1R3, respectively. Amino acids interact with SG's mainly by forming hydrogen bonds with the hydroxyl group of glucose moieties. Significant variation in docked poses of all the SG's were found. In this study, we have proposed the mechanism of the sweetness of the SG's in the form of multiple point stimulation model by considering the diverse binding patterns of various SG's, as well as their structural features. It will give further insight in understanding the differences in the quality of taste and will be used to improve the taste of SG's using semi-synthetic approaches. ? 2015 Elsevier Ltd. All rights reserved.Item Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy.(Elsevier, 2015) Mayank; Jaitak, VikasCancer is responsible for millions of deaths throughout the world every year. Increased understanding as well as advancements in the therapeutic aspect seems suboptimal to restrict the huge deaths associated with cancer. The major cause responsible for this is high resistance as well as relapse rate associated with cancers. Several evidences indicated that cancer stem cells (CSC) are mainly responsible for the resistance and relapses associated with cancer. Furthermore, agents targeting a single protein seem to have higher chances of resistance than multitargeting drugs. According to the concept of network model, partial inhibition of multiple targets is more productive than single hit agents. Thus, by fusing both the premises that CSC and single hit anticancer drugs, both are responsible for cancer related resistances and screened alkaloids for the search of leads having CSC targeting ability as well as the capability to modulating multiple target proteins. The in silico experimental data indicated that emetine and cortistatin have the ability to modulate hedgehog (Hh) pathway by binding to sonic hedgehog (Hh), smoothened (Smo) and Gli protein, involved in maintenance CSCs. Furthermore, solamargine, solasonine and tylophorine are also seems to be good lead molecules targeting towards CSCs by modulating Hh pathway. Except solamargine and solasonine, other best lead molecules also showed acceptable in silico ADME profile. The predicted lead molecules can be suitably modified to get multitargeting CSC targeting agent to get rid of associate resistances.Item Phytochemical investigation of natural sweetener from stevia rebaudiana (Bartoni)(Central University of Punjab, 2014) Mayank; Jaitak, VikasS. rebaudiana is an important plant because of the high concentration of steviol glycosides (SGs). Sugars and artificial sweeteners, which are used in general as well as in pharmaceutical field have shown multiple toxic effects. On the other hand SGs have shown sweetness profile many fold compared to sucrose along with many health benefits.The substitution of SGs as sweeteners seems to be a reasonable solution towards the safety issues. The antidiabetic activity of S. rebaudiana extract as well as SGs is well documented in literature. The association of diabetes with cancer is also well known factor. Taking in consideration the above mentioned factors we have investigated the anticancer potential of extracts of S. rebaudiana. Extracts was prepared using petrolieum ether, ethyl acetate, methanol, aqueous methanol and water. Three cell lines (A-549, H-460 and MCF-7) have been used to evaluate the anticancer potential using MTT assay. In case of A-549, MVE-5 showing IC50 value of 10 ?g/ml. Moreover, IC50 values of MVE-2 was also comparatively better and found to be less than 50 ?g/ml and MVE-4 had shown IC50 value of 90 ?g/ml. In case of H- 460 reasonably better IC50 have been observed for MVE-4 and MVE-5 which is 88 ?g/ml and 92 ?g/ml, respectively. In H-460 reasonably better IC50 have been observed for MVE-4 and MVE-5 which is 88 ?g/ml and 92 ?g/ml, respectively. But in case of MCF-7 breast cancer cell line MVE-1 and MVE-2 have shown IC50 value of 90 ?g/ml and 53 ?g/ml, respectively. Thus, various extracts have shown good antiproliferative activity and S. rebaudiana can be further investigated for its anticancer potential. Furthermore docking study on EGFR, v PI3K and mTOR receptor revealed that SGs have good binding affinity towards all the three mentioned receptors and can be suitably modified to explore its anticancer potential. Moreover unfavourable ADME profile can be overcome by structure modification. Thus on the basis of in-vitro and in-silico data we can conclude that S. rebaudiana extracts have promising anticancer potential. Further isolation of compounds have also been done successfully and total seven compounds have been isolated. Two compounds MVR-1 and MVR-5 have been successfully characterized and found to be quercetin and stevioside respectively which are already known compounds. Many reported SGs have shown poorer taste quality. Moreover taste quality of all SGs are different from one another. Thus docking studies were performed on SGs by constructing homology models of T1R2 and T1R3 subunits of human sweet taste receptors to explore the sweetness mechanism. Ramachandran plot, PROCHECK results and ERRAT overall quality factor indicated the acceptable quality of models. The binding pattern indicated that Asn 44, Ans 52, Ala 345, Pro 343, Ile 352, Gly 346, Gly 47, Ala 354, Ser 336, Thr 326 and Ser 329 are the main interacting amino acids residues of T1R2 and Arg 56, Glu105, Asp 215, Asp 216, Glu 148, Asp 258, Lys 255, Ser 104,Glu 217, Leu 51, Arg 52 of T1R3 respectively. Amino acids interact with SGs mainly by forming hydrogen bonds with hydroxyl group of glucose moieties. Maximum binding affinity has been obtained with SGs having total four glucose molecules attached with it and increase or decrease in glucose molecules reduced the binding afinityThere is significant variation in docked poses of all SGs. Taking in consideration the diverse binding patterns of various SGs as well as their structural features, we have proposed the mechanism of sweetness in the form of multiple point stimulation model. The present study will be helpful to know the proper mechanism of sweetness as well as binding patterns of SGs to sweet taste receptor. It will further helpful in understanding the difference in taste quality and will be used in improving the taste of SGs using semisynthetic approaches.Item Precisely designed oxazolonaphthoimidazo[1,2-a]pyridine-based sensor for the detection of Fe3+ and DCP with cell imaging application(Elsevier B.V., 2023-05-17T00:00:00) Kathuria, Vishal; Kiran; Rani, Payal; Mayank; Joshi, Gaurav; Kumar, Roshan; Sindhu, Jayant; Kumar, Parvin; Negi, Arvind; Kumar, SudhirTwo new turn-off fluorescent sensors (V3 and V4) presented in the article revealed the potential application for the precise detection of Fe3+ and diethylchlorophosphate (DCP). These sensors include oxazolonaphthoimidazo[1,2-a]pyridine scaffold integrated with anthracene and pyrene-based framework. This design has facilitated the twisted intramolecular charge transfer (TICT) and planarised intramolecular charge transfer (PLICT) mechanisms, which were confirmed using computational and photophysical studies. The V3 and V4 fluorescent probes were particularly sensitive and highly selective for detecting Fe3+ and DCP analytes. For Fe3+, V3 and V4 undergo turn-off mechanism with the detection limit of 14.1 and 4.5 nM, respectively. Intracellular detection of Fe3+ via confocal live cell imaging was also demonstrated, showing its application under intracellular conditions. Our experimental data revealed the promises of V3 and V4 for instantaneous, accurate and on-spot monitoring of Fe3+ and DCP, even in the presence of other interfering analytes. � 2023 Elsevier B.V.Item Precisely designed oxazolonaphthoimidazo[1,2-a]pyridine-based sensor for the detection of Fe3+ and DCP with cell imaging application(Elsevier B.V., 2023-05-17T00:00:00) Kathuria, Vishal; Kiran; Rani, Payal; Mayank; Joshi, Gaurav; Kumar, Roshan; Sindhu, Jayant; Kumar, Parvin; Negi, Arvind; Kumar, SudhirTwo new turn-off fluorescent sensors (V3 and V4) presented in the article revealed the potential application for the precise detection of Fe3+ and diethylchlorophosphate (DCP). These sensors include oxazolonaphthoimidazo[1,2-a]pyridine scaffold integrated with anthracene and pyrene-based framework. This design has facilitated the twisted intramolecular charge transfer (TICT) and planarised intramolecular charge transfer (PLICT) mechanisms, which were confirmed using computational and photophysical studies. The V3 and V4 fluorescent probes were particularly sensitive and highly selective for detecting Fe3+ and DCP analytes. For Fe3+, V3 and V4 undergo turn-off mechanism with the detection limit of 14.1 and 4.5 nM, respectively. Intracellular detection of Fe3+ via confocal live cell imaging was also demonstrated, showing its application under intracellular conditions. Our experimental data revealed the promises of V3 and V4 for instantaneous, accurate and on-spot monitoring of Fe3+ and DCP, even in the presence of other interfering analytes. � 2023 Elsevier B.V.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 Structural Diversity of D-Alanine: D-Alanine Ligase and Its Exploration in Development of Antibacterial Agents Against the Multi-Variant Bacterial Infections(John Wiley and Sons Inc, 2022-04-07T00:00:00) Mayank; Sidhu, Jagpreet Singh; Joshi, Gaurav; Sindhu, Jayant; Kaur, Navneet; Singh, NarinderD-alanine: D-alanine ligase (Rv2981c or Ddl) (EC 6.3.2.4) is a bacterial protein that performs critical functions for the proper growth and development of bacterial cells. Understanding the activity profile of Ddl within the various strains of the bacteria seems vital in broad-spectrum antimicrobial drug discovery. Therefore, to understand this heterologous nature, we focused on understanding the functional impact of the structural differences in the Ddl protein from Legionella pneumophila and E. coli bacteria. The structural features and dynamic behavior of Ddl, the interaction pattern, and the docking score of the Ddl-ATP/ADP are also found significantly different from each other. In-depth analysis viz molecular dynamics simulation and residue interaction network (RIN) studies provided us the detailed insight into the differences in the Ddl proteins from both the bacteria. In conclusion, understanding the inter-specific differences in the antibiotic targets Ddl in the case of diverse bacterial strains is vital for rationalizing the treatment of these infectious diseases. Therefore, the current work attempts to foresee the development of more efficacious antibacterial agents devoid of emerging resistance to bacterium strains. � 2022 Wiley-VCH GmbH.