Department of Pharmacy
Permanent URI for this collectionhttp://localhost:4000/handle/123456789/1931
Browse
49 results
Search Results
Item S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis(Springer Nature, 2025-04) Sundriyal, Sandeep; Chowdhury, Shibasish; Majumder, SyamantakNitric oxide (NO), a versatile bio-active molecule modulates cellular functions through diverse mechanisms including S-nitrosylation of proteins. Herein, we report S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells, which interplays with its stability and functions. We detect a significant reduction in H3K27me3 upon S-nitrosylation of EZH2 as contributed by the early dissociation of SUZ12 from the PRC2. Moreover, S-nitrosylation of EZH2 causes its cytosolic translocation, ubiquitination, and degradation. Further analysis reveal S-nitrosylation of cysteine 329 induces EZH2 instability, whereas S-nitrosylation of cysteine 700 abrogates its catalytic activity. We further show that S-nitrosylation-dependent regulation of EZH2 maintains endothelial homeostasis in both physiological and pathological settings. Molecular dynamics simulation reveals the inability of SUZ12 to efficiently bind to the SAL domain of EZH2 upon S-nitrosylation. Taken together, our study reports S-nitrosylation-dependent regulation of EZH2 and its associated PRC2 complex, thereby influencing the epigenetics of endothelial homeostasis.Item Harnessing antimalarial chemical space: the way forward(Taylor & Francis, 2025-10) Sundriyal, SandeepMalaria remains a major health challenge, with increasing resistance to frontline chemotherapy. Recent cheminformatics studies have revealed that potent antiplasmodials occupy a distinct antimalarial chemical space (AMCS), defined by specific property cutoffs.Item Design and synthesis of non-hydroxamate lipophilic inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR): in silico, in vitro and antibacterial studies(RSC, 2024-08) Sundriyal, Sandeep1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway operating in several pathogens, including Mycobacterium and Plasmodium. Since a DXR homologue is not present in humans, it is an important antimicrobial target. Fosmidomycin (FSM) and its analogues inhibit DXR function by chelating the divalent metal (Mn2+ or Mg2+) in its active site via a hydroxamate metal binding group (MBG). The latter, however, enhances the polarity of molecules and is known to display metabolic instability and toxicity issues. While attempts have been made to increase the lipophilicity of FSM by substituting the linker chain and prodrug approach, very few efforts have been made to replace the hydroxamate group with other lipophilic MBGs. We report a systematic in silico and experimental investigation to identify novel MBGs for designing non-hydroxamate lipophilic DXR inhibitors. The SAR studies with selected MBG fragments identified novel inhibitors of E. Coli DXR with IC50 values ranging from 0.29 to 106 μM. The promising inhibitors were also screened against ESKAPE pathogens and M. tuberculosis.Item S-nitrosylation of EZH2 at C329 and C700 interplay with PRC2 complex assembly, methyltransferase activity, and EZH2 stability to regulate endothelial functions(2024) Sundriyal, Sandeep; Chowdhury, Shibasish; Majumder, SyamantakNitric oxide (NO), a versatile bio-active molecule modulates cellular function through diverse mechanisms including S-nitrosylation of proteins. However, the role of this post-translational modification in regulating epigenetic pathways was very limitedly explored. Herein, we report that NO causes S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells (EC) resulting in SUZ12 dissociation from EZH2 bound PRC2 complex, reduced methyltransferase activity, and diminished nuclear localization eventually hampering its stability. We detected a significant reduction in H3K27me3 upon exposure to NO as contributed by the early dissociation of SUZ12 from the PRC2 complex. Longer exposure to NO donors caused EZH2 cytosolic translocation, its ubiquitination, and further degradation primarily through the autophagosome-lysosome pathway. Through in silico S-nitrosylation prediction analysis and site-directed mutagenesis assay, we identified three cysteine residues namely at locations 260, 329, and 700 in EZH2 and further determined that S-nitrosylation of cysteine 329 induced EZH2 instability while S-nitrosylation of cysteine 700 abrogated EZH2’s catalytic activity. A double mutant of EZH2 containing mutations at Cysteine 329 and 700 remained undeterred to NO exposure. Furthermore, reinforcing H3K27me3 in NO exposed EC through the use of an inhibitor of H3K27me3 demethylase, we confirmed a significant contribution of the EZH2-H3K27me3 axis in defining NO-mediated regulation of endothelial gene expression and migration. Molecular dynamics simulation study revealed SUZ12’s inability in efficiently binding to the SAL domain of EZH2 upon S-nitrosylation of C329 and C700. Taken together, our study for the first-time reports that S-nitrosylation dependent regulation of EZH2 and its associated PRC2 complex influences endothelial homeostasis.Item Introduction to health informatics (hi): enhancing healthcare through information technology(Springer, 2024) Sundriyal, SandeepHealth informatics (HI) is an interdisciplinary field that integrates data science, information technology, and healthcare to enhance the administration and delivery of healthcare services. It includes the storage, visualization, and analytics of electronic health records, thus assisting in improving patient care, enhancing clinical decision-making, facilitating data exchange, and supporting research and public health initiatives. This chapter provides an overview of the fundamental concepts of HI and its role in reforming the healthcare system. The basic challenges and ethical issues in implementing HI are also examined in this chapter. In addition, glimpses of HI's research and development activities are provided, employing the case study of the COVID-19 pandemic. This chapter would be helpful for beginners as well as healthcare professionals to get acquainted with the principles and applications of HI.Item Environmental sustainability and its impact on public health(Springer, 2024-09) Sundriyal, SandeepThis book chapter provides a comprehensive review of the relationship between environmental sustainability and public health. It explores the various environmental factors that affect public health, discusses the pathways through which these factors impact human well-being, and highlights the potential benefits of environmental sustainability initiatives in improving public health outcomes. The chapter presents case studies and examples of successful interventions, identifies challenges and barriers to achieving environmental sustainability, and offers recommendations for promoting sustainable practices to enhance public health. In this chapter, the intersection of environmental sustainability and public health has been explored, highlighting the interdependencies and impacts between the two. A holistic and interconnected approach is needed to address environmental and health challenges. For improved acceptance, implementation, and environmental sustainability, it is advised to translate or disseminate research-based solutions into practice.Item Basic nitrogen (BaN): a ‘privileged element’ in medicinal chemistry(Taylor & Francis, 2024-10) Sundriyal, SandeepMedicinal chemists continuously search for small molecules with ideal pharmacokinetic and pharmacodynamic (PKPD) profiles. This quest has resulted in several efforts to understand and define ‘druglikeness’ or ‘drug-like chemical space’. Favorable drug-living system interactions ultimately depend on a compound's chemical structure. Hence, studying patterns and correlations between compound structure and PKPD parameters to derive common denominators is an obvious strategy [Citation1]. Since the publication of ‘Lipinski’s rule of five’ [Citation2], our understanding of the correlation between druglikeness and different physicochemical properties has evolved. Consequently, several guidelines have been suggested for selecting ‘quality’ compounds to improve success rates in preclinical and clinical studies.Item Unlocking the immunomodulatory potential of rosmarinic acid isolated from punica granatum l. Using bioactivity-guided approach: in silico, in vitro, and in vivo approaches(Bentham Science, 2024-11) Sundriyal, SandeepPunica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. Aim: This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. Methods: Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. Results: Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. Conclusion: Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.Item Multicomponent reactions (MCRs) yielding medicinally relevant rings: a recent update and chemical space analysis of the scaffolds(RSC, 2025-01) Sundriyal, SandeepIn this review we have compiled multicomponent reactions (MCRs) that produce cyclic structures. We have covered articles reported since 2019 to showcase the recent advances in this area. In contrast to other available reviews on this topic, we focus specifically on MCRs with strong prospects in medicinal chemistry. Consequently, the reactions operating in a single-pot and yielding novel rings or new substitution patterns under mild conditions are highlighted. Moreover, MCRs that do not require special reagents or catalysts and yield diverse products from commercially available building blocks are reviewed. The synthetic schemes, substrate scope, and other key aspects such as regio- and stereoselectivity are discussed for each MCR. Using cheminformatic tools, we have also attempted to characterize the chemical space of the scaffolds obtained from these MCRs. We show that the MCR scaffolds are novel, more complex, and globular in shape compared to the approved drugs and clinical candidates. Thus, our review represents a step towards identifying and characterizing the novel ring space that can be accessed efficiently through MCRs in a short timeframe.Item Design, synthesis and in vitro evaluation of primaquine and diaminoquinazoline hybrid molecules against the malaria parasite(Wiley, 2025-01) Sundriyal, Sandeep; Roy, AniruddhaIn this study, we built on the known inhibitory potential of diaminoquinazolines (DAQs) against different stages of Plasmodium development and designed a convenient two-step synthesis to combine DAQ with primaquine (PQ) pharmacophore. The PQ-DAQ hybrids displayed potent in vitro activities in the low nanomolar range (IC50 135.20–398.80 nM) against all intra-erythrocytic stages of the drug-sensitive 3D7 strain, with significant potency enhancement compared to PQ alone (IC50 9370 nM). These hybrids were also potent at killing drug-resistant strains (Dd2, Dd2 R539T, IPC4912, CamWT C580Y, and 7G8) in the nanomolar range, with 11 f being the most effective compound (IC50 172.20–396.60 nM). Notably, for the first time, we present evidence that the DAQ-based compound 8 and its hybrids can inhibit β-hematin formation in vitro with potency (IC50 0.90–27.80 μM), suggesting hemozoin formation to be one of the potential targets of this series. Lastly, two hybrids with potent antiplasmodial activity were also found to be safe up to 10 μM against human HepG2 cells, suggesting the possibility of achieving host vs parasite selectivity with this series.