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Molecular Diversity May 2024Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited...
Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited treatment options and the absence of vaccines. The agent responsible for visceral leishmaniasis, also referred to as "black fever" in India, is Leishmania donovani. This study focuses on L. donovani Minichromosome maintenance 10 (LdMcm10), a crucial protein in the DNA replication machinery, as a potential therapeutic target in Leishmania therapy using in silico and in vitro approaches. We employed bioinformatics tools, molecular docking, and molecular dynamics simulations to predict potential inhibitors against the target protein. The research revealed that the target protein lacks homologues in the host, emphasizing its potential as a drug target. Ligands from the DrugBank database were screened against LdMcm10 using PyRx software. The top three compounds, namely suramin, vapreotide, and pasireotide, exhibiting the best docking scores, underwent further investigation through molecular dynamic simulation and in vitro analysis. The observed structural dynamics suggested that LdMcm10-ligand complexes maintained consistent binding throughout the 300 ns simulation period, with minimal variations in their backbone. These findings suggest that these three compounds hold promise as potential lead compounds for developing new drugs against leishmaniasis. In vitro experiments also demonstrated a dose-dependent reduction in L. donovani viability for suramin, vapreotide, and pasireotide, with computed IC values providing quantitative metrics of their anti-leishmanial efficacy. The research offers a comprehensive understanding of LdMcm10 as a drug target and provides a foundation for further investigations and clinical exploration, ultimately advancing drug discovery strategies for leishmaniasis treatment.
PubMed: 38722455
DOI: 10.1007/s11030-024-10876-y -
Molecular Informatics Mar 2024Tuberculosis (TB) is the second leading cause of mortality after COVID-19, with a global death toll of 1.6 million in 2021. The escalating situation of drug-resistant...
Tuberculosis (TB) is the second leading cause of mortality after COVID-19, with a global death toll of 1.6 million in 2021. The escalating situation of drug-resistant forms of TB has threatened the current TB management strategies. New therapeutics with novel mechanisms of action are urgently required to address the current global TB crisis. The essential mycobacterial primase DnaG with no structural homology to homo sapiens presents itself as a good candidate for drug targeting. In the present study, Mitoxantrone and Vapreotide, two FDA-approved drugs, were identified as potential anti-mycobacterial agents. Both Mitoxantrone and Vapreotide exhibit a strong Minimum Inhibitory Concentration (MIC) of ≤25μg/ml against both the virulent (M.tb-H37Rv) and avirulent (M.tb-H37Ra) strains of M.tb. Extending the validations further revealed the inhibitory potential drugs in ex vivo conditions. Leveraging the computational high-throughput multi-level docking procedures from the pool of ~2700 FDA-approved compounds, Mitoxantrone and Vapreotide were screened out as potential inhibitors of DnaG. Extensive 200 ns long all-atoms molecular dynamic simulation of DnaGDrugs complexes revealed that both drugs bind strongly and stabilize the DnaG during simulations. Reduced solvent exposure and confined motions of the active centre of DnaG upon complexation with drugs indicated that both drugs led to the closure of the active site of DnaG. From this study's findings, we propose Mitoxantrone and Vapreotide as potential anti-mycobacterial agents, with their novel mechanism of action against mycobacterial DnaG.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; DNA Primase; Mitoxantrone; Somatostatin
PubMed: 38123523
DOI: 10.1002/minf.202300284 -
Indian Journal of Cancer 2023Postoperative pancreatic fistula (POPF) is the most feared complication following pancreatic resection. Octreotide, a synthetic somatostatin analog, has been widely used... (Review)
Review
Postoperative pancreatic fistula (POPF) is the most feared complication following pancreatic resection. Octreotide, a synthetic somatostatin analog, has been widely used by pancreatic surgeons worldwide after pancreatic resections, often as per surgeon's discretion, to prevent POPF especially in cases at high risk of developing POPF. We herein analyze the data available till date of the subject. A PubMed search with keywords "somatostatin OR octreotide OR somatostatin analogues AND postoperative pancreatic fistula" was made. Further filters were applied in the search "Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Systematic Review, from 1990 - 2021," and the 68 results thus obtained were analyzed and included in this narrative review. There is considerable heterogeneity among the studies assessing the role of octreotide in the prevention of POPF making data comparison difficult, and hence results remain inconclusive. Most of the earlier studies used different definitions of POPF and other complications; included patients with varied pancreatic pathologies such as cancer, chronic pancreatitis, and benign lesions; surgical techniques such as pancreaticoduodenectomy, distal pancreatectomy, and other procedures; use of somatostatin and its analogs such as octreotide, lanreotide, pasireotide, and vapreotide; varied surgeon and institutional volume; and so on. Besides, pancreatic surgery is per se a complex surgical procedure and has its own inherent biases related to patient and the pancreas itself affecting the overall outcome. Data indicate favorable role of newer somatostatin analogs, and further studies are urgently needed. The question about the efficacy of prophylactic octreotide to reduce POPF after pancreaticoduodenectomy remains open to debate.
Topics: Humans; Octreotide; Pancreas; Pancreatectomy; Pancreatic Fistula; Pancreaticoduodenectomy; Postoperative Complications; Randomized Controlled Trials as Topic; Risk Factors; Somatostatin; Treatment Outcome
PubMed: 37530235
DOI: 10.4103/ijc.IJC_280_21 -
Neurotoxicity Research Dec 2022Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses. The aim of this study was to investigate the effect of...
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses. The aim of this study was to investigate the effect of somatostatin analogue Vapreotide in an in vitro Alzheimer's model and its effects based on the relationship between somatostatinergic transmission and neurodegenerative functions. In this study, tau transfection was performed using the MAPT gene cloned into the pcDNA3.1 vector and transfection reagent into the SH-SY5Y cell line. In viability experiments using 10 µM Memantine as a positive control, it was observed that Vapreotide at 50 µM (p < 0.0001) and 100 µM (p < 0.05) had a protective effect on cell viability, 100 µM CYN154806 was found to decrease (p < 0.05) cell viability. It was determined that Vapreotide, decreased the expression levels (50 µM-p < 0.001; 100 µM-p < 0.001; 200 µM-p < 0.0001) and phosphorylation of Tau and p-Tau proteins by western blots. With the qRT-PCR method, it was found that Vapreotide, decreased the BAX/BCL2 (50 µM-p < 0.001; 100 µM-p < 0.01; 200 µM-p < 0.001) expression level and decreased the expression level (50 µM-p < 0.01; 100 µM-p < 0.01; 200 µM-p < 0.001) of the APOE4 gene, which constitutes a genetic risk for AD. This study demonstrates a potential therapeutic role for a somatostatin analogue Vapreotide in Alzheimer's disease.
Topics: Humans; Alzheimer Disease; Neuroprotective Agents; Amyloid beta-Peptides; Neurodegenerative Diseases; Cell Line, Tumor; Neuroblastoma; tau Proteins; Somatostatin; Transfection; Phosphorylation
PubMed: 36378411
DOI: 10.1007/s12640-022-00588-2 -
Pancreatology : Official Journal of the... Dec 2020Postoperative pancreatic fistula/POPF is the most feared complication in pancreatic surgery. Although several systematic reviews investigated the impact of somatostatin... (Meta-Analysis)
Meta-Analysis
Do somatostatin-analogues have the same impact on postoperative morbidity and pancreatic fistula in patients after pancreaticoduodenectomy and distal pancreatectomy? - A systematic review with meta-analysis of randomized-controlled trials.
OBJECTIVE
Postoperative pancreatic fistula/POPF is the most feared complication in pancreatic surgery. Although several systematic reviews investigated the impact of somatostatin analogues on POPF, no stratification was performed regarding type of pancreatic resection (pancreaticoduodenectomy/PD; distal pancreatectomy/DP) and different somatostatin analogues.
METHODS
This study was planed according to the Preferred-Reporting-Items-for-Systematic -Review-and-Meta-Analysis/PRISMA-guidelines. After screening databases for randomized controlled trials/RCT, studies were stratified into pancreatic resection techniques and data were pooled in meta-analyses containing subgroups of octreotide, somatostatin, lanreotide, pasireotide and vapreotide.
RESULTS
The meta-analysis of studies with a mixed cohort of patients after pancreatic resection revealed a protective effect of somatostatin analogues for morbidity (RR: 0.71, p < .00001) but not for mortality (RR: 1.07, = 0.78) or intra-abdominal abscesses (RR: 1.00, p = 1.00). Moreover, no effect was visible for mortality (RR: 1.57, p = .15), morbidity (RR: 0.87, p = .15) and intra-abdominal abscesses (RR: 0.92, p = .48) after PD. The meta-analysis of patients after PD revealed no impact of somatostatin analogues on POPF (RR: 0.87, p = .19) and clinically relevant POPF (RR: 0.69, p = .30). However, treatment with somatostatin analogues in the mixed cohort showed less POPF (RR: 0.60, p < .00001) and clinically relevant POPF (RR: 0.47, p = .02), which was also the case after DP (RR: 0.41, p = .03).
CONCLUSION
Somatostatin analogues did not affect POPF and clinically relevant POPF after PD, but seemed to be associated with less POPF after DP. As no sufficiently powered RCT could be identified by the systematic review, further RCTs are urgently needed to investigate the effect of somatostatin analogues after DP.
STUDY REGISTRATION
CRD42018099808.
Topics: Anastomosis, Surgical; Humans; Morbidity; Pancreas; Pancreatectomy; Pancreatic Fistula; Pancreaticoduodenectomy; Postoperative Complications; Postoperative Period; Somatostatin
PubMed: 33121847
DOI: 10.1016/j.pan.2020.10.043 -
Archives of Medical Science : AMS 2020The extreme health and economic problems in the world due to the SARS-CoV-2 infection have led to an urgent need to identify potential drug targets for treating...
INTRODUCTION
The extreme health and economic problems in the world due to the SARS-CoV-2 infection have led to an urgent need to identify potential drug targets for treating coronavirus disease 2019 (COVID-19). The present state-of-the-art tool-based screening was targeted to identify drug targets among clinically approved drugs by uncovering SARS-CoV-2 helicase inhibitors through molecular docking analysis.
MATERIAL AND METHODS
Helicase is a vital viral replication enzyme, which unwinds nucleic acids and separates the double-stranded nucleic acids into single-stranded nucleic acids. Hence, the SARS-CoV-2 helicase protein 3D structure was predicted, validated, and used to screen the druggable targets among clinically approved drugs such as protease inhibitor, nucleoside reverse transcriptase inhibitor, and non-nucleoside reverse transcriptase inhibitors, used to treat HIV infection using molecular docking analysis.
RESULTS
Interaction with SARS-CoV-2 helicase, approved drugs, vapreotide (affinity: -12.88; score: -9.84 kcal/mol), and atazanavir (affinity: -11.28; score: -9.32 kcal/mol), approved drugs for treating AIDS-related diarrhoea and HIV infection, respectively, are observed with significantly low binding affinity and MOE score or binding free energy. The functional binding pockets of the clinically approved drugs on SARS-CoV-2 helicase protein molecule suggest that vapreotide and atazanavir may interrupt the activities of the SARS-CoV-2 helicase.
CONCLUSIONS
The study suggests that vapreotide may be a choice of drug for wet lab studies to inhibit the infection of SARS-CoV-2.
PubMed: 32399096
DOI: 10.5114/aoms.2020.94567 -
Drug Development and Industrial Pharmacy May 2020Even so, the metal nanoparticles (metal NPs) have attractive optical and biomedical applications, the translation of metal NPs into the clinical practice remains a...
Even so, the metal nanoparticles (metal NPs) have attractive optical and biomedical applications, the translation of metal NPs into the clinical practice remains a challenge due to their severe accumulation in the body. Active targeting to renal podocytes opens the door for enhancing kidney targeting and clearance. The goal of this study was to assess the excretion of larger particle size through kidney podocyte active targeting. To reach this goal, PEGylated quantum dots (QDs) were coated with vapreotide (VAP) for selectively reaching somatostatin receptors (SSTRs) expressed in the podocyte cells. This QDs-VAP was tested on isolated primary podocytes, while the flow cytometry (FACS), confocal microscopy (CLSM), and inductively coupled plasma mass spectrometry (ICP-MS) were used to confirm this hypothesis. The results showed highly specific interactions with podocyte cells as detected by FACS, and CLSM. Moreover, ICP-MS demonstrated higher amount of QDs in the podocyte cells one-hour post-incubation (67.99% ID/g tissue), while the unmodified QDs did not accumulate. This study confirmed that QDs-VAP can target the podocyte's SSTRs then can be cleared podocyte cells. Moreover, these results are considered as a highly promising approach for future therapy, targeting, clearance, and diagnosis of podocyte-associated diseases.
Topics: Analgesics; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Elimination Routes; Female; Metal Nanoparticles; Mice; Mice, Inbred C57BL; Podocytes; Protein Binding; Quantum Dots; Receptors, Somatostatin; Somatostatin
PubMed: 32250174
DOI: 10.1080/03639045.2020.1752710 -
Nanotechnology Jan 2020A key challenge in developing an ethanol oxidation reaction is nontoxic fabrication of highly active stable and low-cost catalysts. Here we design a green synthetic...
A key challenge in developing an ethanol oxidation reaction is nontoxic fabrication of highly active stable and low-cost catalysts. Here we design a green synthetic strategy of AgPd bimetallic nanosphere by a dual-template cascade method. The Pd nanoshell is firstly prepared using Vapreotide acetate as a primary template, and then the Ag nanoshell acts as a secondary template for the distribution of AgPd alloy nanoparticles. The AgPd nanoparticles have core-shell structures and various sizes, and their shell thicknesses are tuned by controlling the amount of PdCl. The six different samples are prepared, named AgPd-1, AgPd-2, AgPd-3, AgPd-4, AgPd-5, and AgPd-6, respectively. The mass current density of AgPd-5, is higher 3.87 times that of commercial Pd/C, and exhibits the best ethanol oxidation reaction activity and long-term stability. The main reasons are that the AgPd-5 possessed excellent specific surface area due to their rough structure, and Ag can remove more CO-like species. This is the first time a Vapreotide acetate/Ag-template method has been used to synthesize a AgPd core-shell structure, which would have broad application prospects for direct ethanol fuel cells.
PubMed: 31557747
DOI: 10.1088/1361-6528/ab4836 -
World Journal of Surgery Jul 2019Prophylactic administration of somatostatin analogues (SA) to reduce the incidence of post-operative pancreatic fistula (POPF) remains contentious. This meta-analysis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Prophylactic administration of somatostatin analogues (SA) to reduce the incidence of post-operative pancreatic fistula (POPF) remains contentious. This meta-analysis evaluated its impact on outcomes following pancreaticoduodenectomy (PD).
METHODS
The EMBASE, MEDLINE and Cochrane databases were searched for randomised controlled trials (RCTs) investigating prophylactic SA following PD. Comparative effects were summarised as odds ratio and weighted mean difference based on an intention to treat. Quantitative pooling of the effect sizes was derived using the random-effects model.
MAIN RESULTS
Twelve RCTs were included involving 1615 patients [SA-treated group (n = 820) and control group (n = 795)]. The SA used included somatostatin-14, pasireotide, vapreotide and octreotide. Pooling of the data showed no significant benefit of its use for the primary outcome measure of all grades of POPF, odds ratio (OR) 0.73 [95% confidence interval (CI), 0.51-1.05, p = 0.09] and clinically relevant POPF, OR 0.48 [95% CI, 0.22-1.06, p = 0.07]. There were no benefits in the secondary outcome measures of delayed gastric emptying, OR 0.98 [95% CI, 0.57-1.69, p = 0.94]; infected abdominal collections, OR 0.80 [95% CI, 0.44-1.43, p = 0.80]; reoperation rates, OR 1.24 [95% CI, 0.73-2.13, p = 0.42]; duration of hospital stay, - 0.23 [95% CI - .59 to 1.13, p = 0.74]; and mortality, 1.78 [95% CI, 0.94-3.39, p = 0.08].
CONCLUSION
SA did not improve the post-operative outcomes following PD, including reducing the incidence of POPF. The routine administration of SA cannot be recommended following PD.
Topics: Antineoplastic Agents, Hormonal; Gastroparesis; Humans; Length of Stay; Octreotide; Pancreatic Fistula; Pancreaticoduodenectomy; Postoperative Complications; Randomized Controlled Trials as Topic; Reoperation; Somatostatin
PubMed: 30798417
DOI: 10.1007/s00268-019-04956-6