Browsing by Author "Thareja, Suresh"

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    Amino Acid Derived Prodrugs: An Approach to Improve the Bioavailability of Clinically Approved Drugs
    (Bentham Science Publishers, 2021-06-04T00:00:00) Singh, Yogesh; Saklani, Samriti; Tantra, Tanmoy; Thareja, Suresh
    Amino acids derived prodrugs emerged as an attractive approach to improve oral delivery of drugs with low solubility and permeability. Conjugation of amino acids with parent drug molecules resulted in several-fold increases in water solubility. Acceptability of the amino acids derived prodrug approach increases day by day to fulfill the different characteristics needed to get the desired pharmacological or therapeutic activity. Due to the significant structural diversity of amino acids, various amino acids can be employed as a carrier to provide desirable Pharmacokinetic-Phar-macodynamic (PK-PD) characteristics. The present review focused on using amino acids as a carrier moiety to improve approved drugs' bioavailability. Attempts have been made to cover amino acid conjugated clinically available drugs. � 2021 Bentham Science Publishers.
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    Bioanalytical Applications of Graphene Quantum Dots for Circulating Cell-Free Nucleic Acids: A Review
    (American Chemical Society, 2022-10-26T00:00:00) Ratre, Pooja; Jain, Bulbul; Kumari, Roshani; Thareja, Suresh; Tiwari, Rajnarayan; Srivastava, Rupesh Kumar; Goryacheva, Irina Yu; Mishra, Pradyumna Kumar
    Graphene quantum dots (GQDs) are carbonaceous nanodots that are natural crystalline semiconductors and range from 1 to 20 nm. The broad range of applications for GQDs is based on their unique physical and chemical properties. Compared to inorganic quantum dots, GQDs possess numerous advantages, including formidable biocompatibility, low intrinsic toxicity, excellent dispensability, hydrophilicity, and surface grating, thus making them promising materials for nanophotonic applications. Owing to their unique photonic compliant properties, such as superb solubility, robust chemical inertness, large specific surface area, superabundant surface conjugation sites, superior photostability, resistance to photobleaching, and nonblinking, GQDs have emerged as a novel class of probes for the detection of biomolecules and study of their molecular interactions. Here, we present a brief overview of GQDs, their advantages over quantum dots (QDs), various synthesis procedures, and different surface conjugation chemistries for detecting cell-free circulating nucleic acids (CNAs). With the prominent rise of liquid biopsy-based approaches for real-time detection of CNAs, GQDs-based strategies might be a step toward early diagnosis, prognosis, treatment monitoring, and outcome prediction of various non-communicable diseases, including cancers. � 2022 American Chemical Society. All rights reserved.
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    Boron in cancer therapeutics: An overview
    (Elsevier Inc., 2023-10-17T00:00:00) Kulkarni, Swanand; Bhandary, Dyuti; Singh, Yogesh; Monga, Vikramdeep; Thareja, Suresh
    Boron 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.
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    Carbon-Based Fluorescent Nano-Biosensors for the Detection of Cell-Free Circulating MicroRNAs
    (MDPI, 2023-02-06T00:00:00) Ratre, Pooja; Nazeer, Nazim; Kumari, Roshani; Thareja, Suresh; Jain, Bulbul; Tiwari, Rajnarayan; Kamthan, Arunika; Srivastava, Rupesh K.; Mishra, Pradyumna Kumar
    Currently, non-communicable diseases (NCDs) have emerged as potential risks for humans due to adopting a sedentary lifestyle and inaccurate diagnoses. The early detection of NCDs using point-of-care technologies significantly decreases the burden and will be poised to transform clinical intervention and healthcare provision. An imbalance in the levels of circulating cell-free microRNAs (ccf-miRNA) has manifested in NCDs, which are passively released into the bloodstream or actively produced from cells, improving the efficacy of disease screening and providing enormous sensing potential. The effective sensing of ccf-miRNA continues to be a significant technical challenge, even though sophisticated equipment is needed to analyze readouts and expression patterns. Nanomaterials have come to light as a potential solution as they provide significant advantages over other widely used diagnostic techniques to measure miRNAs. Particularly, CNDs-based fluorescence nano-biosensors are of great interest. Owing to the excellent fluorescence characteristics of CNDs, developing such sensors for ccf-microRNAs has been much more accessible. Here, we have critically examined recent advancements in fluorescence-based CNDs biosensors, including tools and techniques used for manufacturing these biosensors. Green synthesis methods for scaling up high-quality, fluorescent CNDs from a natural source are discussed. The various surface modifications that help attach biomolecules to CNDs utilizing covalent conjugation techniques for multiple applications, including self-assembly, sensing, and imaging, are analyzed. The current review will be of particular interest to researchers interested in fluorescence-based biosensors, materials chemistry, nanomedicine, and related fields, as we focus on CNDs-based nano-biosensors for ccf-miRNAs detection applications in the medical field. � 2023 by the authors.
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    Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids
    (MDPI, 2022-08-30T00:00:00) Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Sonawane, Pankaj; Paliwal, Harshali; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Jaremko, Mariusz; Emwas, Abdul-Hamid; Yadav, Jagat Pal; Verma, Amita; Khalilullah, Habibullah; Kumar, Pradeep
    Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011�2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer. � 2022 by the authors.
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    Current development of 1,2,3-triazole derived potential antimalarial scaffolds: Structure- activity relationship (SAR) and bioactive compounds
    (Elsevier Masson s.r.l., 2023-07-30T00:00:00) Abdul Rahman, S. Maheen; Bhatti, Jasvinder Singh; Thareja, Suresh; Monga, Vikramdeep
    Malaria is among one of the most devastating and deadliest parasitic disease in the world claiming millions of lives every year around the globe. It is a mosquito-borne infectious disease caused by various species of the parasitic protozoan of the genus Plasmodium. The indiscriminate exploitation of the clinically used antimalarial drugs led to the development of various drug-resistant and multidrug-resistant strains of plasmodium which severely reduces the therapeutic effectiveness of most frontline medicines. Therefore, there is urgent need to develop novel structural classes of antimalarial agents acting with unique mechanism of action(s). In this context, design and development of hybrid molecules containing pharmacophoric features of different lead molecules in a single entity represents a unique strategy for the development of next-generation antimalarial drugs. Research efforts by the scientific community over the past few years has led to the identification and development of several heterocyclic small molecules as antimalarial agents with high potency, less toxicity and desired efficacy. Triazole derivatives have become indispensable units in the medicinal chemistry due to their diverse spectrum of biological profiles and many triazole based hybrids and conjugates have demonstrated potential in vitro and in vivo antimalarial activities. The manuscript compiled recent developments in the medicinal chemistry of triazole based small heterocyclic molecules as antimalarial agents and discusses various reported biologically active compounds to lay the groundwork for the rationale design and discovery of triazole based antimalarial compounds. The article emphasised on biological activities, structure activity relationships, and molecular docking studies of various triazole based hybrids with heterocycles such as quinoline, artemisinins, naphthyl, naphthoquinone, etc. as potential antimalarial agents which could act on the dual stage and multi stage of the parasitic life cycle. � 2023 Elsevier Masson SAS
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    Current Insights and Molecular Docking Studies of the Drugs under Clinical Trial as RdRp Inhibitors in COVID-19 Treatment
    (Bentham Science Publishers, 2022-11-08T00:00:00) Pauly, Irine; Singh, Ankit Kumar; Kumar, Adarsh; Singh, Yogesh; Thareja, Suresh; Kamal, Mohammad A.; Verma, Amita; Kumar, Pradeep
    Study Background & Objective: After the influenza pandemic (1918), COVID-19 was declared a Vth pandemic by the WHO in 2020. SARS-CoV-2 is an RNA-enveloped single-stranded virus. Based on the structure and life cycle, Protease (3CLpro), RdRp, ACE2, IL-6, and TMPRSS2 are the major targets for drug development against COVID-19. Pre-existing several drugs (FDA-approved) are used to inhibit the above targets in different diseases. In coronavirus treatment, these drugs are also in different clinical trial stages. Remdesivir (RdRp inhibitor) is the only FDA-approved medicine for coronavirus treatment. In the present study, by using the drug repurposing strategy, 70 preexisting clinical or under clinical trial molecules were used in scrutiny for RdRp inhibitor potent molecules in coronavirus treatment being surveyed via docking studies. Molecular simulation studies further confirmed the binding mechanism and stability of the most potent compounds. Material and Methods: Docking studies were performed using the Maestro 12.9 module of Schrodinger soft-ware over 70 molecules with RdRp as the target and remdesivir as the standard drug and further confirmed by simulation studies. Results: The docking studies showed that many HIV protease inhibitors demonstrated remarkable binding interactions with the target RdRp. Protease inhibitors such as lopinavir and ritonavir are effective. Along with these, AT-527, ledipasvir, bicalutamide, and cobicistat showed improved docking scores. RMSD and RMSF were further analyzed for potent ledipasvir and ritonavir by simulation studies and were identified as potential candidates for corona disease. Conclusion: The drug repurposing approach provides a new avenue in COVID-19 treatment. � 2022 Bentham Science Publishers.
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    Current Insights into the Role of BRAF Inhibitors in Treatment of Melanoma
    (Bentham Science Publishers, 2022-06-28T00:00:00) Singh, Ankit Kumar; Kumar, Adarsh; Thareja, Suresh; Kumar, Pradeep
    Melanomas represent only 4% of all skin cancers, but their mortality rate is more than 50 % of any other skin cancer. Alteration in genetic and environmental factors are the risk factors for melanoma development. The RAS/RAF/MEK/ERK or Mitogen-activated protein kinase (MAPK) pathway is activated in melanoma. BRAF activation is necessary to govern differentiation, proliferation, and survival. Mutations in BRAF were found in 80�90% of all melanomas. Over 90% of BRAF mutations occur at codon 600, and over 90% of them are BRAFV600E other common mutations are BRAFV600K, BRAFV600R, BRAF V600?E2?, and BRAF V600D. Based on ?C-helix and DFG motif (?C-helix-IN/DFG-IN), (?C-helix-IN/DFG-OUT), (?C-helix-OUT/DFG-IN) and (?C-helix-OUT/ DFG-OUT) are four structural types of inhibitors for targeting BRAF. Sorafenib, Vemurafenib, Dabrafenib, and Encorafenib are FDA-approved for the treatment of BRAF. Understanding melanoma pathogenesis, RAS/RAF/MEK/ERK or MAPK path-way, and BRAF conformations, mutations, the problems with FDA approved BRAF inhibitors will be important for new drug discovery, modification of existing BRAF barriers to improve target specific action, and prevent increasing response levels while minimizing toxicity. � 2023 Bentham Science Publishers.
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    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 Kumar
    The 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.
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    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, Vikramdeep
    Introduction: 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.
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    Dual aromatase-steroid sulfatase inhibitors (DASI's) for the treatment of breast cancer: a structure guided ligand based designing approach
    (Taylor and Francis Ltd., 2022-12-13T00:00:00) Singh, Yogesh; Jaswal, Shalini; Singh, Satwinder; Verma, Sant Kumar; Thareja, Suresh
    Dual aromatase-steroid sulfatase inhibitors (DASIs) lead to significant deprivation of estrogen levels as compared to a single target inhibition and thereby exhibited an additive or synergistic effect in the treatment of hormone-dependent breast cancer (HDBC). Triazole-bearing DASI�s having structural features of clinically available aromatase inhibitors are identified as lead structures for optimization as DASI�s. To identify the spatial fingerprints of target-specific triazole as DASI�s, we have performed molecular docking assisted Gaussian field-based comparative 3D-QSAR studies on a dataset with dual aromatase-STS inhibitory activities. Separate contours were generated for both aromatase and steroid sulphates showing respective pharmacophoric structural requirements for optimal activity. These developed 3D-QSAR models also showed good statistical measures with the excellent predictive ability with PLS-generated validation constraints. Comparative steric, electrostatic, hydrophobic, HBA, and HBD features were elucidated using respective contour maps for selective target-specific favourable activity. Furthermore, the molecular docking was used for elucidating the mode of binding as DASI�s along with the MD simulation of 100 ns revealed that all the protease-ligand docked complexes are overall stable as compared to reference ligand (inhibitor ASD or Irosustat) complex. Further, the MM-GBSA study revealed that compound 24 binds to aromatase as well as STS active site with relatively lower binding energy than reference complex, respectively. A comparative study of these developed multitargeted QSAR models along with molecular docking and dynamics study can be employed for the optimization of drug candidates as DASI�s. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
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    Dual Aromatase-Sulphatase Inhibitors (DASIs) for the Treatment of Hormone Dependent Breast Cancer
    (Bentham Science Publishers, 2021-01-19T00:00:00) Banjare, Laxmi; Jain, Akhlesh Kumar; Thareja, Suresh
    Breast cancer is the most frequently diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an alarming rate. The level of estrogens in breast cancer tissues of postmenopausal women is 10-40 folds higher than the non-carcinogenic breast tissues. As a result of this greater level of estrogen, breast tissue becomes more prone to develop breast cancer; mainly, estradiol plays a significant role in the initiation and development of hormone-dependent breast cancer. Androstenedione, Adrenal dehydroepiandrosterone sulfate, and estrone-sulfate also play an important role as precursors for estrogen biosynthesis. Estrogen deprivation exhibits an attractive phenomenon in the advancement of ideal therapeutics for the treatment of breast cancer. Inhibition of aromatase and sulphatase emerged as an attractive therapy for the treatment of hormone-dependent breast cancer via deprivation of estrogen by different pathways. The cocktail of aromatase and sulphatase inhibitors known as Dual Aromatase-sulphatase Inhibitors (DASIs) emerged as an attractive approach for effective estrogen deprivation. The present review arti-cle focused on the journey of dual aromatase-sulphatase inhibitors from the beginning to date (2020). Keeping in view the key observations, this review may be helpful for medicinal chemists to design and develop new and efficient dual aromatase-sulphatase inhibitors for the possible treatment of hor-mone-related breast cancer. � 2021 Bentham Science Publishers.
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    Elacestrant: a new FDA-approved SERD for the treatment of breast cancer
    (Springer, 2023-05-16T00:00:00) Bhatia, Neha; Thareja, Suresh
    Elacestrant (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.
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    Flavonoids as promising anticancer agents: an in silico investigation of ADMET, binding affinity by molecular docking and molecular dynamics simulations
    (Taylor and Francis Ltd., 2022-09-27T00:00:00) Biharee, Avadh; Yadav, Arpita; Jangid, Kailash; Singh, Yogesh; Kulkarni, Swanand; Sawant, Devesh M.; Kumar, Pradeep; Thareja, Suresh; Jain, Akhlesh Kumar
    Cancer is one of the most concerning diseases to humankind. Various treatment strategies are being employed for its treatment, out of which use of natural products is an essential one. Flavonoids have proven to be promising anticancer targets since decades. Also, tubulin is a significant biological target for the development of anticancer agents due to its crucial role in mitosis and abundance throughout the body. In the current study, in silico ADMET parameters of 104 flavonoids were examined, followed by molecular docking with the colchicine binding site of Tubulin protein (PDB; Id 4O2B). The best conformation from each flavonoid subcategory with the best docking score (MolDock score) was further subjected to 100 ns of molecular dynamics to investigate the protein-ligand complex�s stability. Different parameters such as RMSD, RMSF, rGy and SASA were calculated for the six flavonoids using molecular dynamic studies. The top most compound from all the six subcategories of flavonoids elicited best behavior in the colchicine binding site of Tubulin protein. This in silico study employing molecular docking and molecular dynamics simulation provides strong evidence for flavonoids to be excellent anti-tubulin agents for the treatment of cancer. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
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    Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAFV600E inhibitors
    (Royal Society of Chemistry, 2022-10-21T00:00:00) Singh, Ankit Kumar; Novak, Jurica; Kumar, Adarsh; Singh, Harshwardhan; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Verma, Amita; Yadav, Jagat Pal; Khalilullah, Habibullah; Pathania, Vikas; Nandanwar, Hemraj; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, Pradeep
    The �RAS-RAF-MEK-ERK� pathway is an important signaling pathway in melanoma. BRAFV600E (70-90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (?C-IN/DFG-IN), type II (?C-IN/DFG-OUT), type I1/2 (?C-OUT/DFG-IN), and type I/II (?C-OUT/DFG-OUT). First- and second-generation BRAF inhibitors show resistance to BRAFV600E and are ineffective against malignancies induced by dimer BRAF mutants causing �paradoxical� activation. In the present study, we performed molecular modeling of pyrimidine-sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAFV600E inhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600E inhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of 88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600E protein than previous inhibitors. Similar to the FDA-approved BRAFV600E inhibitors the developed compounds have [?C-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful against BRAFV600E resistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600E selective inhibitors. � 2022 The Royal Society of Chemistry.
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    Gaussian field-based comparative 3D QSAR modelling for the identification of favourable pharmacophoric features of chromene derivatives as selective inhibitors of ALR2 over ALR1
    (Springer, 2021-01-07T00:00:00) Verma, Sant Kumar; Kumar, Niraj; Thareja, Suresh
    Aldehyde reductase (ALR1) and aldose reductase (ALR2) are both oxo-reductase enzymes of aldo-keto reductase (AKR) superfamily involved in several cellular processes. ALR1 plays an important role in colorectal cancer, lungs, and hepatic carcinoma, while ALR2 is involved in diabetic complications like retinopathy, neuropathy, and nephropathy cataract. Both the enzymes take part in distinct physiological processes, however, share more > 70% structural homology. This is the major cause behind the unachieved target selectivity of molecules that entered the development pipeline as ALR2 inhibitors. Chromene analogues have been widely explored for diverse biological activities, including antioxidant and diabetic complication prevention potential. For the identification of spatial fingerprints of target-specific chromene bearing ALR2 inhibitors over ALR1, Gaussian field-based comparative 3D QSAR models were generated on a dataset having ALR1 and ALR2 inhibitory activity. Both the ALR1 and ALR2 3D QSAR models were statistically fit with good predictive ability concerning PLS generated validation constraints. The comparative steric, electrostatic, hydrophobic, HBA, and HBD features were elucidated using respective contour maps for selective target specific favourable activity against ALR2 over ALR1. In addition, the five-point pharmacophores for ALR1 and ALR2 favourable features were also generated using the DHHRR_1 hypothesis for better insight on the distinctive features of ALR2 inhibitors compared to ALR1. � 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
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    In silico docking of anti cancerous drugs with ?-cyclodextrin polymer as a prominent approach to improve the bioavailability
    (Bentham Science Publishers, 2020-10-14T00:00:00) Jain, Akhlesh K.; Mishra, Keerti; Thareja, Suresh
    Background: ?-Cyclodextrin, a cyclic oligosaccharides having 7 macrocyclic rings of glucose subunits usually linked together by ?-1,4 glycosidic bond, bears characteristic chemical structure, with an exterior portion as hydrophilic to impart water solubility and interior cavity as hydrophobic, for hosting the hydrophobic molecules. Objective: In the present work binding affinities and interactions between various anti-cancerous drugs and ?cyclodextrin using molecular docking simulations was examined for the bioavailability enhancement of cytotoxic drugs through improved solubility for the treatment of breast cancer. Methods: Molegro Virtual Docker, an integrated software was used for the prediction and estimation of interaction between ?-cyclodextrin and anti cancerous drugs. Results: Out of tested anti cancerous drug, Olaparib having pyridopyridazione scaffold possess highest MolDock (-130.045) and Re-ranks score (-100.717), ensuring strong binding affinity. However, 5-Fluoro Uracil exhibited the lowest MolDock score (-61.0045), indicating weak or no binding affinity, while few drugs showed no H-bond interaction with the ?-cyclodextrin. Conclusion: The binding conformations of anti cancerous drugs obtained from the present study can be selected for the development of improved formulation having superior solubility which will lead to attain better pharmacological profile with negligible toxicity. � 2021 Bentham Science Publishers.
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    In silico molecular interaction studies of chitosan polymer with aromatase inhibitor: Leads to letrozole nanoparticles for the treatment of breast cancer
    (Bentham Science Publishers, 2020-08-26T00:00:00) Mishra, Keerti; Verma, Sant K.; Ratre, Pooja; Banjare, Laxmi; Jain, Abhishek; Thareja, Suresh; Jain, Akhlesh K.
    Background: It takes a lot more studies to evaluate the molecular interaction of nanoparticles with the drug, their drug delivery potential and release kinetics. Thus, we have taken in silico and in vitro approaches into account for the evaluation of the drug delivery ability of the chitosan nanoparticles. Objective: The present work was aimed to study the interaction of chitosan nanoparticles with appropriate aromatase inhibitors using in silico tools. Further, synthesis and characterization of chitosan nanoparticles having optimal binding energy and affinity between drug and polymer in terms of size, encapsulation efficiency were carried out. Methods: In the current study, molecular docking was used to map the molecular interactions and estimation of binding energy involved between the nanoparticles and the drug molecules in silico. Letrozole is used as a model cytotoxic agent currently being used clinically; hence Letrozole loaded chitosan nanoparticles were formulated and characterized using photomicroscope, particle size analyzer, scanning electron microscope and fourier transform infra-red spectroscopy. Results: Letrozole had the second-highest binding affinity within the core of chitosan with MolDock (-102.470) and Re-rank (-81.084) scores. Further, it was investigated that formulated nanoparticles were having superior drug loading capacity and high encapsulation efficiency. In vitro drug release study exhibited prolonged release of the drug from chitosan nanoparticles. Conclusion: Results obtained from the in silico and in vitro studies suggest that Letrozole loaded nanoparticles are ideal for breast cancer treatment. � 2021 Bentham Science Publishers.
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    An Insight to Heat Shock Protein 90: A Remedy for Multiple Problems
    (Bentham Science Publishers, 2022-08-30T00:00:00) Yadav, Megha; Singh, Ankit Kumar; Kumar, Adarsh; Thareja, Suresh; Kumar, Pradeep
    Heat shock protein 90 (Hsp90) is a chaperone protein that prevents many other proteins from aggre-gating by folding them in a certain way. Hsp90 consists of three structural domains: N-terminal, middle and C-terminal domains. Hsp90 has many activities in numerous proteins and signaling pathways like chimeric fusion proteins, steroid hormone receptors, tumor suppressor genes, and cell cycle regulatory proteins. The role of Hsp90 is not only in cancer but also in other diseases like COVID-19, leishmaniasis, diabetes, flavi virus, systemic sclerosis, grass carp reovirus, psoriasis, malaria, cardiac fibrosis, and alcohol-related liver diseases. This review is a compilation of the pharmacological profile of Hsp90 inhibitors, problems associated with them, and suggested remedies for the same. � 2022 Bentham Science Publishers.
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    Mannose conjugated starch nanoparticles for preferential targeting of liver cancer
    (Bentham Science Publishers, 2020-09-04T00:00:00) Jain, Akhlesh Kumar; Sahu, Hitesh; Mishra, Keerti; Thareja, Suresh
    Aim: To design D-Mannose conjugated 5-Fluorouracil (5-FU) loaded Jackfruit seed starch nanoparticles (JFSSNPs) for site-specific delivery. Background: Liver cancer is the third leading cause of death in the world and the fifth most often diagnosed cancer. It is a major global threat to public health. Treatment of liver cancer with conventional method bears several side effects, thus to undertake these side effects as a formulation chal-lenge, it is necessary to develop novel target-specific drug delivery system for the effective and bet-ter localization of drug into the proximity of target with restricting the movement of the drug in normal tissues. Objective: To optimize and characterize the developed D-Mannose conjugated 5-Fluorouracil (5--FU) loaded Jackfruit seed starch nanoparticles (JFSSNPs) for effective treatment of liver cancer. Materials and Methods: 5-FU loaded JFSSNPs were prepared and optimized formulations having higher encapsulation efficiency were conjugated with D-Mannose. These formulations were characterized for size, morphology, zeta potential, X-Ray Diffraction, and Differential Scanning Calorimetry. The potential of NPs was studied using in vitro cytotoxicity assay, in vivo kinetic studies, and bio-distribution studies. Result and Discussion: 5-Fluorouracil loaded NPs had a particle size between 336 to 802nm with drug entrapment efficiency between 64.2 to 82.3%. In XRD analysis, 5-FU peak was diminished in the diffractogram, which could be attributed to the successful incorporation of the drug in amorp-hous form. DSC study suggests there was no physical interaction between 5-FU and Polymer. NPs showed sustained in vitro 5-FU release up to 2 hours. In vivo, mannose conjugated NPs prolonged the plasma level of 5-FU and assisted in the selective accumulation of 5-FU in the liver (vs. other organs spleen, kidney, lungs, and heart) compared to unconjugated one and plain drug. Conclusion: In vivo, bio-distribution, and plasma profile studies resulted in a significantly higher concentration of 5-Fluorouracil liver, suggesting that these carriers are efficient, viable, and targeted carrier of 5-FU treatment of liver cancer. � 2021 Bentham Science Publishers.