Browsing by Author "Singh, Yogesh"

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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.
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.
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.
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.
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.
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.
Molecular docking, 3D-QSAR and simulation studies for identifying pharmacophoric features of indole derivatives as 17?-hydroxysteroid dehydrogenase type 5 (17?-HSD5) inhibitors
(Taylor and Francis Ltd., 2023-02-06T00:00:00) Kulkarni, Swanand; Singh, Yogesh; Biharee, Avadh; Bhatia, Neha; Monga, Vikramdeep; Thareja, Suresh
Excess of androgens leads to various diseases such as Poly-Cystic Ovarian Syndrome, Prostate Cancer, Hirsutism, Obesity and Acne. 17?-Hydroxysteroid Dehydrogenase type 5 (17?-HSD5) converts androstenedione into testosterone peripherally, thereby significantly contributing to the development of these diseases. Indole-bearing scaffolds are reported as potential 17?-HSD5 inhibitors for the manifestation of diseases arising due to androgen excess. In the present work, we have extensively performed a combination of molecular docking, Gaussian field-based 3D-QSAR, Pharmacophore mapping and MD-simulation studies (100 ns) to identify the pharmacophoric features of indole-based compounds as potent 17?-HSD5 inhibitors. Molecular simulation studies of the most potent compound in the binding pocket of enzyme revealed that the compound 11 was stable in the binding pocket and showed good binding affinity through interactions with various residues of active site pocket. The Molecular mechanics Generalized Born surface area continuum solvation (MM/GBSA) and Molecular mechanics Poisson�Boltzmann surface area (MM/PBSA) calculations revealed that the compound 11 possessed a free binding energy of ?36.36 kcal/mol and ?7.00 kcal/mol, respectively, which was better as compared to reference compound Desmethyl indomethacin (DES). The developed pharmacophore will be helpful to design novel indole-based molecules as potent 17?-HSD5 inhibitors for the treatment of various androgenic disorders. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Molecular dynamics and 3D-QSAR studies on indazole derivatives as HIF-1? inhibitors
(Taylor and Francis Ltd., 2022-03-23T00:00:00) Singh, Yogesh; Sanjay, Kulkarni Swanand; Kumar, Pradeep; Singh, Satwinder; Thareja, Suresh
Hypoxia-inducible factor (HIF) is a transcriptional factor which plays a crucial role in tumour metastasis thereby responsible for development of various forms of cancers. Indazole derivatives have been reported in the literature as potent HIF-1? inhibitor via interaction with key residues of the HIF-1? active site. Taking into consideration the role HIF-1? in cancer and potency of indazole derivative against HIF-1?; it was considered of interest to correlate structural features of known indazole derivatives with specified HIF-1? inhibitory activity to map pharmacophoric features through Three-dimensional quantitative structural activity relationship (3D-QSAR) and pharmacophore mapping. Field and Gaussian based 3D-QSAR studies were performed to realize the variables influencing the inhibitory potency of HIF-1? inhibitors. Field and Gaussian- based 3D-QSAR models were validated through various statistical measures generated by partial least square (PLS). The steric and electrostatic maps generated for both 3D-QSAR provide a structural framework for designing new inhibitors. Further; 3D-maps were also helpful in understanding variability in the activity of the compounds. Pharmacophore mapping also generates a common five-point pharmacophore hypothesis (A1D2R3R4R5_4) which can be employed in combination with 3D-contour maps to design potent HIF-1? inhibitors. Molecular docking and molecular dynamics (MD) simulation of the most potent compound 39 showed good binding efficiency and was found to be quite stable in the active site of the HIF-1? protein. The developed 3D-QSAR models; pharmacophore modelling; molecular docking studies along with the MD simulation analysis may be employed to design lead molecule as selective HIF-1? inhibitors for the treatment of Cancer. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
Multifaceted 3D-QSAR analysis for the identification of pharmacophoric features of biphenyl analogues as aromatase inhibitors
(Taylor and Francis Ltd., 2021-12-29T00:00:00) Banjare, Laxmi; Singh, Yogesh; Verma, Sant Kumar; Singh, Atul Kumar; Kumar, Pradeep; Kumar, Shashank; Jain, Akhlesh Kumar; Thareja, Suresh
Aromatase, a cytochrome P450 enzyme, is responsible for the conversion of androgens to estrogens, which fuel the multiplication of cancerous cells. Inhibition of estrogen biosynthesis by aromatase inhibitors (AIs) is one of the highly advanced therapeutic approach available for the treatment of estrogen-positive breast cancer. Biphenyl moiety aids lipophilicity to the conjugated scaffold and enhances the accessibility of the ligand to the target. The present study is focused on the investigation of, the mode of binding of biphenyl with aromatase, prediction of ligand-target binding affinities, and pharmacophoric features essential for favorable for aromatase inhibition. A multifaceted 3D-QSAR (SOMFA, Field and Gaussian) along with molecular docking, molecular dynamic simulations and pharmacophore mapping were performed on a series of biphenyl bearing molecules (1�33) with a wide range of aromatase inhibitory activity (0.15�920 nM). Among the generated 3D-QSAR models, the Force field-based 3D-QSAR model (R 2 = 0.9151) was best as compared to SOMFA and Gaussian Field (R 2=0.7706, 0.9074, respectively). However, all the generated 3D-QSAR models were statistically fit, robust enough, and reliable to explain the variation in biological activity in relation to pharmacophoric features of dataset molecules. A four-point pharmacophoric features with three acceptor sites (A), one aromatic ring (R) features, AAAR_1, were obtained with the site and survival score values 0.890 and 4.613, respectively. The generated 3D-QSAR plots in the study insight into the structure�activity relationship of dataset molecules, which may help in the designing of potent biphenyl derivatives as newer inhibitors of aromatase. Communicated by Ramaswamy H. Sarma. � 2021 Informa UK Limited, trading as Taylor & Francis Group.
Pharmacophore derived 3D-QSAR, molecular docking, and simulation studies of quinoxaline derivatives as ALR2 inhibitors
(Taylor and Francis Ltd., 2023-09-12T00:00:00) Singh, Yogesh; Kumar, Niraj; Kulkarni, Swanand; Singh, Satwinder; Thareja, Suresh
Aldose Reductase 2 (ALR2), a key enzyme of the polyol pathway, plays a crucial role in the pathogenesis of diabetic complications. Quinoxaline scaffold-based compounds have been identified as potential ALR2 inhibitors for the management of diabetic complications. In the present work, molecular dynamic simulation studies in conjugation with pharmacophore mapping and atom-based 3D-QSAR were performed on a dataset of 99 molecules in comparison with Epalrestat (reference) to mark the desirable structural features of quinoxaline analogs to generate a probable template for designing novel and effective ALR2 inhibitors. The most potent compound 81 was subjected to MD simulation studies and found to be stable, with better interactions with the binding pocket as compared to Epalrestat. The MM-GBSA and MM-PBSA calculations showed that compound 81 possessed binding free energies of ?35.96 and ?4.92 kcal/mol, respectively. Atom-based 3D-QSAR yielded various pharmacophoric features with excellent statistical measures, such as correlation coefficient (R 2 value), F-value (Fischer ratio), Q 2 value (cross-validated correlation coefficient), and Pearson�s R-value for training and test sets. Furthermore, the pharmacophore mapping provided a five-point hypothesis (AADRR) and docking analysis revealed the active ligand-binding orientations on the active site�s amino acid residues TYR 48, HIE 110, TRP 111, and TRP 219. The results of this study will help in designing potent inhibitors of ALR2 for the management of diabetic complications. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Phosphate Prodrugs: An Approach to Improve the Bioavailability of Clinically Approved Drugs
(Bentham Science Publishers, 2023-02-09T00:00:00) Tantra, Tanmoy; Singh, Yogesh; Patekar, Rohan; Kulkarni, Swanand; Kumar, Pradeep; Thareja, Suresh
The phosphate prodrug approach has emerged as a viable option for increasing the bioavailability of a drug candidate with low hydrophilicity and poor cell membrane permeability. When a phosphoric acid moiety is attached to the parent drug, it results in a several-fold elevation in aqueous solubility which helps to achieve desired bioavailability of the pharmaceutically active parental molecule. The neutral phosphate prodrugs have rapid diffusion ability through the plasma membrane as compared to their charged counterpart. The presence of phosphate mono ester breaking alkaline phosphatase (ALP) enzyme throughout the whole human body, is the main consideration behind the development of phosphate prodrug strategy. The popularity of this phosphate prodrug strategy is increasing nowadays due to the fulfillment of different desired pharmacokinetic characteristics required to get pharmaceutical and therapeutic responses without showing any serious adverse drug reactions (ADR). This review article mainly focuses on various phosphate prodrugs synthesized within the last decade to get an improved pharmacological response of the parent moiety along with various preclinical and clinical challenges associated with this approach. Emphasis is also given to the chemical mechanism to release the parent moiety from the prodrug. � 2024 Bentham Science Publishers.
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, Suresh
Polycystic 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 Ltd
Recent Advancements in the Discovery of MDM2/MDM2-p53 Interaction Inhibitors for the Treatment of Cancer
(Bentham Science Publishers, 2022-11-16T00:00:00) Bhatia, Neha; Khator, Rakesh; Kulkarni, Swanand; Singh, Yogesh; Kumar, Pradeep; Thareja, Suresh
Discovery of MDM2 and MDM2-p53 interaction inhibitors changed the direction of anticancer research as it is involved in about 50% of cancer cases globally. Not on-ly the inhibition of MDM2 but also its interaction with p53 proved to be an effective strategy in anticancer drug design and development. Various molecules of natural as well as synthetic origin have been reported to possess excellent MDM2 inhibitory potential. The present review discusses the pathophysiology of the MDM2-p53 interaction loop and MDM2/MDM2-p53 interaction inhibitors from literature covering recent patents. Focus has also been put on characteristic features of the active site of the target and its desired interactions with the currently FDA-approved inhibitor. The designing approach of previ-ously reported MDM2/MDM2-p53 interaction inhibitors, their SAR studies, in silico studies, and the biological efficacy of various inhibitors from natural as well as synthetic origins are also elaborated. An attempt is made to cover recently patented MDM2/MD-M2-p53 interaction inhibitors. � 2023 Bentham Science Publishers.
Selective Estrogen Receptor Modulators (SERMs) for the treatment of ER+ breast cancer: An overview
(Elsevier B.V., 2022-08-02T00:00:00) Das, Sweety; Kulkarni, Swanand; Singh, Yogesh; Kumar, Pradeep; Thareja, Suresh
Breast cancer is a major threat to women's lives throughout the world. Hormone-dependent or estrogen-receptor positive (ER+) breast cancer accounts for more than 80% of all instances. Selective Estrogen Receptor Modulators (SERMs), which specifically control the ERs and limit the progression of breast malignancy, have drawn the interest of researchers in the treatment of breast cancer by regulation of the estrogen receptors (ER), particularly ER?. The mode of action, anti-proliferative potential, SAR, and favourable interactions of the potent candidates are elaborated. Many potent SERMs with diversity in structural space have been rationally designed and reported in the literature for their anti-breast cancer activity. These SERMs exhibited remarkable anti-proliferative activity against ER+ BC. Since, ER? is responsible for the initiation and progression of BC, there is an urgent need to strategically design and synthesize new SERMs, having more selective binding towards ER?. Long term use of traditionally marketed SERMs is associated with several adverse effects, such as development of endometrial cancer and other disorders. Insight of structural features in the present review will prove to be a guideline for the researchers to design and develop potent SERMs for the treatment of ER+ breast cancer. � 2022 Elsevier B.V.
Thioether linkage chemistry: perspectives and prospects in therapeutic designing
(Elsevier, 2023-07-07T00:00:00) Singh, Yogesh; Kulkarni, Swanand; Thareja, Suresh
Polymer�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.