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Yesterday, 18 Ιουλίου 2016, 8:33:23 πμ
Rhodomyrtone Target Exploration: Computer Aided Search on Staphylococcus aureus Key Proteins as a Potential Therapeutic Target
Yesterday, 18 Ιουλίου 2016, 8:33:28 πμ
Background: Methicillin-resistant Staphylococcus aureus (MRSA) has been a global public health problem because MRSA infection often leads to poor clinical outcomes. Currently, the search for an effective candidate has been ongoing. Rhodomyrtone, a natural compound, has been exhibited strong anti-MRSA activity comparable to that of vancomycin, a drug of choice for MRSA treatment. An important procedure to develop the compound in clinical use is elucidation of its molecular mechanism. However, previous attempts were performed to clarify the mechanism but ambiguity still exists. With this aspect, computer aided techniques to identify drug targets is able to enhance a success rate in drug discovery. </p><p> Methods: Fifty MRSA proteins, playing roles in vital processes, was screened rhodomyrtone molecular targets. The molecular docking study was operated using AutoDock4. To confirm two possible targets, checkerboard assay and cell visualization were further carried out. </p><p> Results: Rhodomyrtone exhibited an interesting efficacy towards one-fifth of the given proteins. Moreover, metaldependent phosphate binding proteins were excluded from possible targets because of electrostatic forces. Amongst chosen proteins, rhodomyrtone, both enantiomers, displayed significant potency to dihydrofolate reductase (DHFR) and filamenting temperature-sensitive Z (FtsZ) proteins, compared to their natural substrates/inhibitors. However, protein cofactors such as nicotinamide adenine dinucleotide phosphate or guanosine diphosphate decreased rhodomyrtone binding affinity. This information suggested a cofactor free DHFR and a ligand-unbound FtsZ are likely to prove to be rhodomyrtone targets for MRSA inhibition. In addition, checkerboard assay and cell visualization gave a hint on target confirmation. </p><p> Conclusion: We have proposed potential rhodomyrtone targets, and DHFR and FtsZ caught our interest. Further studies will need to focus on profound molecular information concerning the rhodomyrtone response to these proteins, both in experimental and computational views. </p><p>
Characterizing the Zika Virus Genome – A Bioinformatics Study
Yesterday, 18 Ιουλίου 2016, 8:33:28 πμ
Background: The recent epidemic of Zika virus infections in South and Latin America have raised serious concern on its ramifications for the population in the Americas and spread of the virus worldwide. The Zika virus disease is a relatively new phenomenon for which sufficient and comprehensive data and investigative reports have not been available to date. </p><p> Objective: To carry out a bioinformatics study of the available Zika virus genomic sequences to characterize the virus. </p><p> Method: 2D graphical representation method is used for visual rendering and compute sequence parameters and descriptors of the African and Asian-American groups of the Zika viruses to characterize the sequences. We also used MEGA5.2 and other software to compute various biological properties of interest like phylogenetic relationships, transition-transversion ratios, amino acid usage, codon usage bias and hydropathy index of the Zika genomes and virions. </p><p> Results: The phylogenetic relationships show that the African and Asian-American Zika virus genomes are grouped in two clades. The 2D plots of typical genomes of these types also show dramatic differences indicating that the gene sequences at the 5’-end coding regions for the structural proteins are rather strongly conserved. Among other characteristics, the transition/transversion ratio matrices for the sequences in each of the two clades show that analogous to the dengue virus, the transition rates are about 10 to 15 times the transversion rates. </p><p> Conclusion: These findings are important for computer-assisted approaches towards surveillance of emerging Zika virus strains as well as in the design of drugs and vaccines to combat the growth and spread of the Zika virus. </p><p>
Design of Broad-Spectrum Inhibitors of Influenza A Virus M2 Proton Channels: A Molecular Modeling Approach
Yesterday, 18 Ιουλίου 2016, 8:33:28 πμ
Background: The influenza A virus M2 proton channel plays a critical role in its life cycle. However, known M2 inhibitors have lost their clinical efficacy due to the spread of resistant mutant channels. Thus, the search for broad-spectrum M2 channel inhibitors is of great importance. </p><p> Objective: The goal of the present work was to develop a general approach supporting the design of ligands interacting with multiple labile targets and to propose on its basis the potential broad-spectrum inhibitors of the M2 proton channel. </p><p> Method: The dynamic dimer-of-dimers structures of the three primary M2 target variants, wild-type, S31N and V27A, were modeled by molecular dynamics and thoroughly analyzed in order to define the inhibitor binding sites. The potential inhibitor structures were identified by molecular docking and their binding was verified by molecular dynamics simulation. </p><p> Results: The binding sites of the M2 proton channel inhibitors were analyzed, a number of potential broad-spectrum inhibitors were identified and the binding modes and probable mechanisms of action of one promising compound were clarified. </p><p> Conclusion: Using the molecular dynamics and molecular docking techniques, we have refined the dynamic dimer-ofdimers structures of the WT, S31N and V27A variants of the M2 proton channel of the influenza A virus, analyzed the inhibitor binding sites, identified a number of potential broad-spectrum inhibitor structures targeting them, and clarified the binding modes and probable mechanisms of action of one promising compound. The proposed approach is also suitable for the design of ligands interacting with other multiple labile targets. </p><p>
Clarification of Interaction Mechanism of Mouse Hepatitis Virus (MHV) N and nsp3 Protein with Homology Modeling and Protein-Protein Docking Analysis
Yesterday, 18 Ιουλίου 2016, 8:33:28 πμ
The coronavirus Nucleocapsid (N) plays an important role in the virus structure, the replication, and the transcription of CoV. This protein, which has a helix and flexible structure, and is capable of binding on to the viral genomic RNA, is a non-structural protein (nsp3). Many studies suggest that the N protein interaction with nsp3 plays a critical role in the virus replication early in infection. Therefore, it is necessary to know the definition of the interaction mechanism of N and nsp3 protein in terms of the CoV replication transcription mechanism. We report on the homology modeling, molecular dynamics simulation, and docking studies to explain the structure-function relationship and the interaction mechanism. In addition, the prototype MHV is preferred in the wet experiment, so we also based our study on the MHV N and nsp3 proteins that belong to the experimental study. The amino acid sequences of MHV N and nsp3 proteins have similarity between human and severe acute respiratory syndrome coronavirus. Therefore, the 3D structure models of these proteins were built with using the crystal structure of the CoV family members as a template. By following these models, molecular dynamics simulations were applied to attain the most stable conformation. Finally, protein-protein docking was performed to prove accuracy of model structures of the MHV N and to clarify the interaction with nsp3. As a result, Lys 113, Arg 125, Tyr 127, Glu 173, Tyr 190 residues that play an important role in virus replication were determined.
The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity
Yesterday, 18 Ιουλίου 2016, 8:33:28 πμ
Background: Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms including deafness, neuropathy, myopathy, hyperlactatemia, lactic acidosis, pancreatitis and lipodystrophy, among others, which could even compromise the life of the patient. </p> <p> Objectives: The aim of this work is to review the potential mitochondrial toxicity derived from drugs used in health care, including anesthetics, antiepileptics, neuroleptics, antidepressants, antivirals, antibiotics, antifungals, antimalarics, antineoplastics, antidiabetics, hypolipemiants, antiarrhythmics, anti-inflammatories and nitric oxide. </p> <p> Methods: We herein have reviewed data from experimental and clinical studies to document the molecular mitochondrial basis, potential biomarkers and putative clinical symptoms associated to secondary effects of drugs. </p> <p> Results: One hundred and forty-five articles were selected and the information was organized by means of the primary target to which pharmacologic drugs were directed. Adverse toxic events were classified depending on the mitochondrial offtarget effect and whether they had been demonstrated in the experimental or clinical setting. </p> <p> Conclusions: Since treatment of acquired mitochondriopathies remains supportive and therapeutic interventions cannot be avoided, information of molecular and clinical consequences of toxic exposure becomes fundamental to assess riskbenefit imbalance of treatment prescription. Additionally, there is a crucial need to develop less mitochondrial toxic compounds, novel biomarkers to follow up mitochondrial toxicity (or implement those already proposed) and new approaches to prevent or revert unintended mitochondrial damage.
Beyond Cholinesterase Inhibition: Anti-Inflammatory Role and Pharmacological Profile of Current Drug Therapy for Alzheimer’s Disease
Πέμπτη, 14 Ιουλίου 2016, 8:56:03 πμ
Inflammation is a common response of an individual against either exogenous or endogenous damage. The role of inflammation and of inflammatory cells recently emerged also in the pathogenesis of neurodegenerative disorders. Experimental evidences show how neurotransmitters, besides their role in the synapses, play a modulatory role during immune response. Drugs used for treatment of dementia symptoms are able to increase neurotransmitters levels, and likely to have a modulatory role during immune response. Aim of this review is to discuss the most recent advances on inflammation role during neurodegeneration and also to individuate the potential anti-inflammatory role played by drugs currently used for Alzheimer’s disease treatment.
Utilization of Evidence-Based Secondary Prevention Medications at the Time of Discharge in Patients with Acute Coronary Syndrome (ACS) in Qatar
Πέμπτη, 14 Ιουλίου 2016, 8:56:03 πμ
Background and Objectives: In Qatar, ACS (Acute Coronary Syndrome) has become the leading cause of morbidity and mortality. Guidelines recommend that ACS patients should receive indefinite treatment with antiplatelets, -blockers, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and statins. The study objectives were to assess the use of evidence-based secondary prevention medication at discharge among ACS patients in Qatar and to determine the clinical and demographic characteristics associated with the use of these medications. </p><p> Setting and Methods: A retrospective medical record review was conducted at the Heart Hospital in Qatar. A random sample of 1068 ACS patients was selected. Patient characteristics were summarized. Prevalence of medications at discharge were computed for each medication as well as for medication combinations. Multiple logistic regression was used to detect patient variables that were associated with the outcomes. A p 0.05 was considered significant. </p><p> Main Outcome Measures: -Percentage of ACS patients discharged on each of the following medications: antiplatelets (aspirin, clopidogrel), -blockers, ACEI or ARBs and statins and on the combination of these medications-Association between the use of these medications and patient characteristics. </p><p> Results: In total, 1064 records were reviewed. The majority were males (85.3%) and about 1 in 5 (18.7%) were Qatari. At discharge, patients were prescribed the following: aspirin (96.0%), clopidogrel (92.0%), -blockers (90.6%) and statins (97.7%). ACEI and ARBs were prescribed to 63.5 and 11.3%, respectively. The concurrent 4 medications (aspirin or clopidogrel, statins or other lowering cholesterol medication, -blockers and ACEI or ARB) were prescribed to 773 patients (77.8%; 95% confidence interval: 75.2-80.4%). Being overweight or obese, and having PCI (percutaneous coronary intervention) or hypertension were associated with higher prescription of the concurrent medications. Those with diabetes had a 52% increase in the odds of prescribing the 4 medications. Those with kidney disease had a 67% reduction in the odds of prescribing. </p><p> Conclusion: Most ACS patients were prescribed antiplatelets, -blockers and statins, but the use of ACEIs or ARBs was suboptimal. Strategies are needed to enhance ACEI or ARB prescribing, especially for high risk patients who would have the greatest therapeutic benefit from these drugs. </p><p>
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