Molecular docking cannot accurately predict drug off-target effects: Implications for the role of voriconazole in the exacerbation of myasthenia gravis

2013 ◽  
Vol 49 (1) ◽  
pp. 147-148
Author(s):  
Spyros N. Deftereos
Keyword(s):  
Molecular Docking ◽  
Myasthenia Gravis ◽  
Target Effects

Short-Term Ultramicronized Palmitoylethanolamide Therapy in Patients with Myasthenia Gravis: a Pilot Study to Possible Future Implications of Treatment

2019 ◽  
Vol 18 (3) ◽  
pp. 232-238 ◽  
Author(s):  
Emanuela Onesti ◽  
Vittorio Frasca ◽  
Marco Ceccanti ◽  
Giorgio Tartaglia ◽  
Maria Cristina Gori ◽  
...  
Keyword(s):  
Pilot Study ◽  
Myasthenia Gravis ◽  
Repetitive Nerve Stimulation ◽  
Beneficial Effects ◽  
Antibody Titers ◽  
The Stability ◽  
Ultramicronized Palmitoylethanolamide ◽  
Open Pilot

Background: The cannabinoid system may be involved in the humoral mechanisms at the neuromuscular junction. Ultramicronized-palmitoylethanolamide (μm-PEA) has recently been shown to reduce the desensitization of Acetylcholine (ACh)-evoked currents in denervated patients modifying the stability of ACh receptor (AChR) function. <p> Objective: To analyze the possible beneficial effects of μm-PEA in patients with myasthenia gravis (MG) on muscular fatigue and neurophysiological changes. <p> Method: The duration of this open pilot study, which included an intra-individual control, was three weeks. Each patient was assigned to a 1-week treatment period with μm-PEA 600 mg twice a day. A neurophysiological examination based on repetitive nerve stimulation (RNS) of the masseteric and the axillary nerves was performed, and the quantitative MG (QMG) score was calculated in 22 MG patients every week in a three-week follow-up period. AChR antibody titer was investigated to analyze a possible immunomodulatory effect of PEA in MG patients. <p> Results: PEA had a significant effect on the QMG score (p=0.03418) and on RNS of the masseteric nerve (p=0.01763), thus indicating that PEA reduces the level of disability and decremental muscle response. Antibody titers did not change significantly after treatment. <p> Conclusion: According to our observations, μm-PEA as an add-on therapy could improve muscular response to fatigue in MG. The possible modulation of AChR currents as a means of eliciting a direct effect from PEA on the conformation of ACh receptors should be investigated. The co-role of cytokines also warrants an analysis. Given the rapidity and reversibility of the response, we suppose that PEA acts directly on AChR, though further studies are needed to confirm this hypothesis.

scholarly journals Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fariba Peytam ◽  
Ghazaleh Takalloobanafshi ◽  
Toktam Saadattalab ◽  
Maryam Norouzbahari ◽  
Zahra Emamgholipour ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Study ◽  
Rat Small Intestine ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Mild Conditions ◽  
Glucosidase Inhibitors ◽  
Inhibitory Activities

AbstractIn an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.

Potential role of thymoma and other mediastinal tumors in the pathogenesis of myasthenia gravis

1993 ◽  
Vol 44 (2) ◽  
pp. 171-176 ◽  
Author(s):  
Makoto Matsui ◽  
Hiromi Wada ◽  
Mitsuhiro Ohta ◽  
Yasuo Kuroda
Keyword(s):  
Myasthenia Gravis ◽  
Potential Role ◽  
Mediastinal Tumors

The Role of Adjuvants in the Efficacy of a Peptide Vaccine for Myasthenia Gravis

2001 ◽  
Vol 226 (4) ◽  
pp. 307-311 ◽  
Author(s):  
James L. McAnally ◽  
Likang Xu ◽  
Matteo Villain ◽  
J. Edwin Blalock
Keyword(s):  
Myasthenia Gravis ◽  
Peptide Vaccine ◽  
Cell Epitope ◽  
Keyhole Limpet Hemocyanin ◽  
Peptide Vaccines ◽  
Lewis Rat ◽  
Cell Responses ◽  
Immunogenic Region ◽  
Experimental Autoimmune

Myasthenia gravis (MG) and its animal model, experimental autoimmune (EA) MG, are caused by interference with neuromuscular transmission by autoantibodies against the nicotinic acetylcholine receptor (AChR) on muscle. Previously, we have shown that two peptides, denoted RhCA 67-16 and RhCA 611-001, designed to be complementary in structure to the main immunogenic region and the dominant Lewis rat T cell epitope (α-chain residues 100-116) of the AChR, respectively, are effective vaccines that prevent EAMG in rats by inducing anti-idiotypic/clonotypic antibodies (Ab) and lowering levels of AChR Ab. These studies employed keyhole limpet hemocyanin (KLH) as a carrier and complete Freunds adjuvant (CFA). In advance of a clinical trial the present study tested the efficacy of RhCA 611-001 when combined with different adjuvants that are approved for use in humans. Adjuvants chosen for comparison were incomplete Freunds adjuvant (IFA) and aluminum hydroxide (Alum). As a second goal we evaluated diphtheria toxin (DT) as an alternative carrier protein to KLH. Alum was found to be an effective adjuvant, particularly when used with the peptide conjugated to DT. This combination of carrier and adjuvant provided protection against EAMG comparable with that observed with CFA and KLH. Using enzyme-linked immunosorbent assays for Ab against RhCA 611-001, it was found that disease protection is qualitatively, but not quantitatively, related to the anti-peptide Ab response. Our results demonstrate a vaccine formulation that should be useful in the first soon-to-be-conducted clinical trials of peptide vaccines to specifically correct aberrant T and B cell responses in an autoimmune disease.

scholarly journals Specificity of RNAi, LNA and CRISPRi as loss-of-function methods in transcriptional analysis

2017 ◽  
Author(s):  
Lovorka Stojic ◽  
Aaron Lun ◽  
Jasmin Mangei ◽  
Patrice Mascalchi ◽  
Valentina Quarantotti ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Noncoding Rna ◽  
Specific Activity ◽  
Transcriptional Analysis ◽  
Clonal Variation ◽  
Loss Of Function ◽  
Negative Controls ◽  
Whole Transcriptome ◽  
Target Effects

ABSTRACTLoss-of-function (LOF) methods, such as RNA interference (RNAi), antisense oligonucleotides or CRISPR-based genome editing, provide unparalleled power for studying the biological function of genes of interest. When coupled with transcriptomic analyses, LOF methods allow researchers to dissect networks of transcriptional regulation. However, a major concern is nonspecific targeting, which involves depletion of transcripts other than those intended. The off-target effects of each of these common LOF methods have yet to be compared at the whole-transcriptome level. Here, we systematically and experimentally compared non-specific activity of RNAi, antisense oligonucleotides and CRISPR interference (CRISPRi). All three methods yielded non-negligible offtarget effects in gene expression, with CRISPRi exhibiting clonal variation in the transcriptional profile. As an illustrative example, we evaluated the performance of each method for deciphering the role of a long noncoding RNA (lncRNA) with unknown function. Although all LOF methods reduced expression of the candidate lncRNA, each method yielded different sets of differentially expressed genes upon knockdown as well as a different cellular phenotype. Therefore, to definitively confirm the functional role of a transcriptional regulator, we recommend the simultaneous use of at least two different LOF methods and the inclusion of multiple, specifically designed negative controls.

α1-Antitrypsin: Key Player or Bystander in Acute Respiratory Distress Syndrome?

2021 ◽  
Vol 134 (5) ◽  
pp. 792-808
Author(s):  
Grace Hogan ◽  
Pierce Geoghegan ◽  
Tomás P. Carroll ◽  
Jennifer Clarke ◽  
Oisín F. McElvaney ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Main Function ◽  
Alveolar Capillary ◽  
Target Effects ◽  
Antiprotease Activity ◽  
The Ideal

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar–capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.

Role of Molecular Docking in Computer-Aided Drug Design and Development

2016 ◽  
pp. 1-28
Author(s):  
Rahul Agarwal ◽  
Ashutosh Singh ◽  
Subhabrata Sen
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Protein Binding ◽  
Design And Development ◽  
Advantages And Disadvantages ◽  
Computer Aided ◽  
Drug Designing ◽  
Near Future

Molecular Docking is widely used in CADD (Computer-Aided Drug Designing), SBDD (Structure-Based Drug Designing) and LBDD (Ligand-Based Drug Designing). It is a method used to predict the binding orientation of one molecule with the other and used for any kind of molecule based on the interaction like, small drug molecule with its protein target, protein – protein binding or a DNA – protein binding. Docking is very much popular technique due to its reliable prediction properties. This book chapter will provide an overview of diverse docking methodologies present that are used in drug design and development. There will be discussion on several case studies, pertaining to each method, followed by advantages and disadvantages of the discussed methodology. It will typically aim professionals in the field of cheminformatics and bioinformatics, both in academia and in industry and aspiring scientists and students who want to take up this as a profession in the near future. We will conclude with our opinion on the effectiveness of this technology in the future of pharmaceutical industry.

scholarly journals Unraveling the role of ectopic thymic tissue in patients undergoing thymectomy for myasthenia gravis

2019 ◽  
Vol 11 (9) ◽  
pp. 4039-4048 ◽  
Author(s):  
Feng Li ◽  
Ya Tao ◽  
Gero Bauer ◽  
Aron Elsner ◽  
Zhongmin Li ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Thymic Tissue
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