Pharmaceutical Sciences and Natural Products - Research Publications
Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56
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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 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 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 Developing our knowledge of the quinolone scaffold and its value to anticancer drug design(Taylor and Francis Ltd., 2023-08-18T00:00:00) Singh, Yogesh; Bhatia, Neha; Biharee, Avadh; Kulkarni, Swanand; Thareja, Suresh; Monga, VikramdeepIntroduction: The quinolone scaffold is a bicyclic benzene-pyridinic ring scaffold with nitrogen at the first position and a carbonyl group at the second or fourth position. It is endowed with a diverse spectrum of pharmacological activities, including antitumor activity, and has progressed into various development phases of clinical trials for their target-specific anticancer activity. Areas covered: The present review covers both classes of quinolones, i.e. quinolin-2(H)-one and quinolin-4(H)-one as anticancer agents, along with their possible mode of binding. Furthermore, their structure-activity relationships, molecular mechanisms, and pharmacokinetic properties are also covered to provide insight into their structural requirements for their rational design as anticancer agents. Expert opinion: Synthetic feasibility and ease of derivatization at multiple positions, has allowed medicinal chemists to explore quinolones and their chemical diversity to discover newer anticancer agents. The presence of both hydrogen bond donor (?NH) and acceptor (-C=O) functionality in the basic scaffold at two different positions, has broadened the research scope. In particular, substitution at the -NH functionality of the quinolone motif has provided ample space for suitable functionalization and appropriate substitution at the quinolone�s third, sixth, and seventh carbons, resulting in selective anticancer agents binding specifically with various drug targets. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Thioether linkage chemistry: perspectives and prospects in therapeutic designing(Elsevier, 2023-07-07T00:00:00) Singh, Yogesh; Kulkarni, Swanand; Thareja, SureshPolymer�drug conjugates (PDCs) are an emerging approach for the development of targeted drug delivery systems for chemotherapeutic agents possessing poor pharmacokinetic properties. Development of PDCs offers an advantage of optimization to a certain extent to formulation as well as medicinal chemists via linking bioactive drug molecule to polymeric linker. Formulation of a drug in PDCs generally enhances the pharmacokinetic parameters of a drug by increasing its bioavailability. Also, controlled and target-specific drug release helps to reduce the adverse effects associated with off-target binding of the drugs. In this chapter, readers will be able to understand thoroughly the concept of PDCs, linkers used in the preparation of PDCs, their types, and various examples of PDCs that are reportedly found to be potent in the diseases they were intended to show activity. � 2023 Elsevier Inc. All rights reserved.Item Virtual screening, structure based pharmacophore mapping, and molecular simulation studies of pyrido[2,3-d]pyrimidines as selective thymidylate synthase inhibitors(Taylor and Francis Ltd., 2023-05-08T00:00:00) Kumar, Adarsh; Novak, Jurica; Singh, Ankit Kumar; Singh, Harshwardhan; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Verma, Amita; Kumar, PradeepHuman thymidylate synthase is the rate-limiting enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate. dUMP (pyrimidine) and folate binding site hTS inhibitors showed resistance in colorectal cancer (CRC). In the present study, we have performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyrido[2,3-d]pyrimidine derivatives to stabilize inactive confirmation of hTS. A library of 42 molecules was designed. Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed. To validate efficacy of the designed molecules, we performed molecular dynamics simulation studies at 1000 ns with principal component analysis and binding free energy calculations on the hTS protein, also drug likeness properties of all hits were in acceptable range. Compounds T36, T39, T40, and T13 interacted with the catalytic amino acid (Cys195), an essential amino acid for anticancer activity. The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Elacestrant: a new FDA-approved SERD for the treatment of breast cancer(Springer, 2023-05-16T00:00:00) Bhatia, Neha; Thareja, SureshElacestrant (RAD-1901), a selective estrogen receptor degrader, was approved by USFDA on January 27, 2023, for the treatment of breast cancer. It has been developed by Menarini Group under the brand name Orserdu�. Elacestrant showed anticancer activity both in vitro and in vivo in ER+ HER2-positive breast cancer models. The present review delebrates the development stages of Elacestrant, with its medicinal chemistry, synthesis, mechanism of action, and pharmacokinetic studies. Clinical data and safety profile has also been discussed, including data from randomized trials. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Selective Estrogen receptor degraders (SERDs) for the treatment of breast cancer: An overview(Elsevier Masson s.r.l., 2023-05-04T00:00:00) Bhatia, Neha; Hazra, Shreejita; Thareja, SureshDiscovery of SERDs has changed the direction of anticancer research, as more than 70% of breast cancer cases are estrogen receptor positive (ER+). Therapies such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI's) have been effective, but due to endocrine resistance, SERDs are now considered essential therapeutics for the treatment of ER+ breast cancer. The present review deliberates the pathophysiology of SERDs from the literature covering various molecules in clinical trials. Estrogen receptors active sites distinguishing characteristics and interactions with currently available FDA-approved drugs have also been discussed. Designing strategy of previously reported SERDs, their SAR analysis, in silico, and the biological efficacy have also been summarized along with appropriate examples. � 2023 Elsevier Masson SASItem Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer�s disease(Taylor and Francis Ltd., 2023-04-28T00:00:00) Jangid, Kailash; Devi, Bharti; Sahoo, Ashrulochan; Kumar, Vijay; Dwivedi, Ashish Ranjan; Thareja, Suresh; Kumar, Rajnish; Kumar, VinodAlzheimer�s disease (AD) is a multifactorial neurological disorder characterized by memory loss and cognitive impairment. The currently available single-targeting drugs have miserably failed in the treatment of AD, and multi-target directed ligands (MTDLs) are being explored as an alternative treatment strategy. Cholinesterase and monoamine oxidase enzymes are reported to play a crucial role in the pathology of AD, and multipotent ligands targeting these two enzymes simultaneously are under various phases of design and development. Recent studies have revealed that computational approaches are robust and trusted tools for identifying novel therapeutics. The current research work is focused on the development of potential multi-target directed ligands that simultaneously inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) enzymes employing a structure-based virtual screening (SBVS) approach. The ASINEX database was screened after applying pan assay interference and drug-likeness filter to identify novel molecules using three docking precision criteria; High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP). Additionally, binding free energy calculations, ADME, and molecular dynamic simulations were employed to get structural insights into the mechanism of protein-ligand binding and pharmacokinetic properties. Three lead molecules viz. AOP19078710, BAS00314308 and BDD26909696 were successfully identified with binding scores of ?10.565, ?10.543 & ?8.066 kcal/mol against AChE and ?11.019, ?12.357 & ?10.068 kcal/mol against MAO-B, better score as compared to the standard inhibitors. In the near future, these molecules will be synthesized and evaluated through in�vitro and in�vivo assays for their inhibition potential against AChE and MAO-B enzymes. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Microsponges as Drug Delivery System: Past, Present, and Future Perspectives(Bentham Science Publishers, 2023-04-04T00:00:00) Biharee, Avadh; Bhartiya, Sudha; Yadav, Arpita; Thareja, Suresh; Jain, Akhlesh KumarMicrosponges are polymeric delivery devices composed of porous microspheres that range in size from 5 to 300 micrometers. These have been explored for biomedical applications such as targeted drug deliv-ery, transdermal drug delivery, anticancer drug delivery, and bone substitutes. The purpose of this study is to conduct a comprehensive analysis of recent developments and prospects for a microsponge-based drug delivery system. The current study analyzes how the Microsponge Delivery System (MDS) is made, how it works, and how it can be used for a wide range of therapeutic purposes. The therapeutic potential and patent information of microsponge-based formulations were systematically analyzed. The authors summarize various effective tech-niques for developing microsponges, such as liquid-liquid suspension polymerization, quasi-emulsion solvent diffusion method, water-in-oil-in-water (w/o/w) emulsion solvent diffusion, oil-in-oil emulsion solvent diffu-sion, lyophilization method, porogen addition method, vibrating orifice aerosol generator method, electro-hydrodynamic atomization method, and ultrasound-assisted microsponge. Microsponge may reduce the side effects and increase drug stability by positively altering drug release. Drugs that are both hydrophilic and hy-drophobic can be loaded into a microsponge and delivered to a specific target. The microsponge delivery technology offers numerous advantages over conventional delivery systems. Microsponges, which are spherical sponge-like nanoparticles with porous surfaces, have the potential to increase the stability of medications. They also efficiently decrease the undesirable effects and alter drug release. � 2023 Bentham Science Publishers.