5 research outputs found
Molecular docking and cytotoxicity interactions of naringenin and its nano-structured lipid carriers in ERα positive breast cancer
No full textPhytoestrogens are known to have beneficial properties in various carcinomas. They exhibit its efficacy at cellular levels. Naringenin a flavonoidal phytoestrogen is been explored for its antioxidant, cardio protective and cytotoxic function. The low absorbtion and poor bioavailability of naringenin makes it less efficient in targeting tumours at cellular levels. Due to the structural similarity of naringenin with estradiol and considering the affinity of naringenin with estrogen receptor, this study explores the interactions of naringenin on important signaling proteins involved in ER positive breast cancer through molecular docking studies and the prepared naringenin solid lipid nano particles were characterized and studied for its preventive potential against breast cancer cell lines. The lipidoid form of phytoestrogen shows promising cytotoxic potential compared with naringenin
Design and synthesis of novel quercetin metal complexes as IL-6 inhibitors for anti-inflammatory effect in SARS-CoV-2
No full text823-835One of the most common causes of mortality in COVID-19 patients is cytokine release syndrome (CRS). Though several cytokines are involved in CRS, the role of Interleukin 6 is significant. Considering the importance of IL-6 inhibition and the drawbacks of the existing monoclonal antibodies, the present study develops new flavonoid metal complexes as immune boosters targeting IL-6 for SARS-CoV-2 treatment. To identify the potential flavonoids from 152 secondary plant metabolites, PyRx 0.9 tool has been used. The top scorer quercetin was converted into quercetin-oxime. Seven metal complexes (QM-1 to QM-7) were made from quercetin-oxime by utilizing divalent metals such as zinc, copper, magnesium, cobalt, barium, and cadmium. It was assumed that all compounds were moderately soluble and would not penetrate the BBB through in silico ADME studies. However, the in vitro heamolytic research revealed a modest heamolytic effect in all seven complexes. To know the IL-6 inhibitory potential preliminary level, the complexes were screened for cytotoxicity in cell lines MCF-7 which predominantly expresses the IL-6 level. The cytotoxic effects of all complexes were considerable relative to the marketable Nutridac formulation. The complexes quercetin-Zinc (QM1) and quercetin-Zinc-Ascorbic acid (QM7) showed significant cytotoxicity on MCF-7 compared to Nutridac and no cytotoxic toward the normal cell lines
Molecular insights in repurposing selective COX-2 inhibitor celecoxib against matrix metalloproteinases in potentiating delayed wound healing: a molecular docking and MMPB/SA based analysis of molecular dynamic simulations
No full textMatrix metalloproteinases (MMPs) are proteolytic enzymes that play a role in healing, including reducing inflammation, promoting fibroblast and keratinocyte migration, and modifying scar tissue. Due to their pleiotropic functions in the wound-healing process in diabetic wounds, MMPs constitute a significant cause of delayed wound closure. COX-2 inhibitors are proven to inhibit inflammation. The present study aims to repurpose celecoxib against MMP-2, MMP-8 and MMP-9 through in silico approaches, such as molecular docking, molecular dynamics, and MMPB/SA analysis. We considered five selective COX-2 inhibitors (celecoxib, etoricoxib, lumiracoxib, rofecoxib and valdecoxib) for our study against MMPs. Based on molecular docking study and hydrogen bonding pattern, celecoxib in complex with three MMPs was further analyzed using 1 µs (1000 ns) molecular dynamics simulation and MMPB/SA techniques. These studies identified that celecoxib exhibited significant binding affinity −8.8, −7.9 and −8.3 kcal/mol, respectively, against MMP-2, MMP-8 and MMP-9. Celecoxib formed hydrogen bonding and hydrophobic (π–π) interactions with crucial substrate pocket amino acids, which may be accountable for their inhibitory nature. The MMPB/SA studies showed that electrostatic and van der Waal energy terms favoured the total free binding energy component, while polar solvation terms were highly disfavored. The in silico analysis of the secondary structures showed that the celecoxib binding conformation maintains relatively stable along the simulation trajectories. These findings provide some key clues regarding the accommodation of celecoxib in the substrate binding S1’ pocket and also provide structural insights and challenges in repurposing drugs as new MMP inhibitors with anti-inflammatory and anti-inflammatory wound-healing properties. Communicated by Ramaswamy H. Sarma</p
In silico approach for uncovering inhibitors of SARS-CoV-2 by targeting TMPRSS2 via molecular networking-based strategies
No full text544-559Understanding the pathogenesis of COVID-19 is vital for developing more effective therapeutic strategies. Among the
key proteases involved in the disease progression are Transmembrane Serine Protease 2 (TMPRSS2) and Disintegrin and
Metalloproteinase 17 (ADAM17), which play critical roles in viral entry and infection. TMPRSS2 facilitates the priming of
the SARS-CoV-2 spike (S) protein, making it a promising target for therapeutic intervention. Alpha-1-antitrypsin (A1AT), a
natural tissue protector with antiviral and anti-inflammatory properties, inhibits TMPRSS2, further underscoring its
importance as a drug target. Given the urgency of addressing the COVID-19 pandemic, repurposing existing FDA-approved
drugs offers a faster and more practical approach than developing new drugs from scratch. This study utilized molecular
networking strategies via Cytoscape version 3.9.1 to screen FDA-approved drugs for potential interactions with TMPRSS2.
A pharmacophore model was subsequently generated, followed by virtual screening and docking studies. From the
molecular networking analysis, 22 compounds were selected based on their binding interactions with TMPRSS2. These
compounds were evaluated using pharmacophore modeling and virtual screening, with further selection based on Lipinski's
rule of five and low RMSD values (below 0.07 Å). Docking studies identified six top-performing molecules from the ZINC
database, with ZINC00896543 and ZINC05316843 exhibiting the highest binding affinities (-22.0254 and -21.676 kcal/mol,
respectively), surpassing the co-crystal ligand (-12.8236 kcal/mol). The findings highlight the potential of these repurposed
compounds for integrated COVID-19 management. Further pharmacokinetic, pharmacodynamic, preclinical, and clinical
studies are warranted to validate these candidates and pave the way for designing new agents with minimal side effects and
enhanced efficacy
Virtual high throughput screening of natural peptides against ErbB1 and ErbB2 to identify potential inhibitors for cancer chemotherapy
No full textHuman epidermal growth factor receptors (EGFR), namely ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4, the trans-membrane family of tyrosine kinase receptors, are overexpressed in many types of cancers. These receptors play an important role in cell proliferation, differentiation, invasion, metastasis and angiogenesis including unregulated activation of cancer cells. Overexpression of ErbB1 and ErbB2 that occurs in several types of cancers is associated with poor prognosis leading to resistance to ErbB1-directed therapies. In this connection, promising strategy to overcome the disadvantages of the existing chemotherapeutic drugs is the use of short peptides as anticancer agents. In the present study, we have performed virtual high throughput screening of natural peptides against ErbB1 and ErbB2 to identify potential dual inhibitors and identified five inhibitors based on their binding affinities, ADMET analysis, MD simulation studies and calculation of free energy of binding. These natural peptides could be further exploited for developing drugs for treating cancer. Communicated by Ramaswamy H. Sarma</p
