scholarly journals In silico structural homology modeling and characterization of multiple N-terminal domains of selected bacterial Tcps

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10143
Author(s):  
Mohammed Alaidarous
Keyword(s):  
Homology Modeling ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Bacterial Pathogens ◽  
Experimental Studies ◽  
Amino Acid Sequences ◽  
Host Immune System ◽  
Modeling Tools ◽  
Tir Domain ◽  
Terminal Domains

Several bacterial pathogens produce Toll/interleukin-1 receptor (TIR) domain-containing protein homologs that are important for subverting the Toll-like receptor (TLR) signaling cascades in hosts. Consequently, promoting the persistence and survival of the bacterial pathogens. However, the exact molecular mechanisms elucidating the functional characteristics of these bacterial proteins are not clear. Physicochemical and homology modeling characterization studies have been conducted to predict the conditions suitable for the stability and purification of these proteins and to predict their structural properties. The outcomes of these studies have provided important preliminary data for the drug discovery pipeline projects. Here, using in silico physicochemical and homology modeling tools, we have reported the primary, secondary and tertiary structural characteristics of multiple N-terminal domains of selected bacterial TIR domain-containing proteins (Tcps). The results show variations between the primary amino acid sequences, secondary structural components and three-dimensional models of the proteins, suggesting the role of different molecular mechanisms in the functioning of these proteins in subverting the host immune system. This study could form the basis of future experimental studies advancing our understanding of the molecular basis of the inhibition of the host immune response by the bacterial Tcps.

scholarly journals Main Structural Targets for Engineering Lipase Substrate Specificity

Catalysts ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 747
Author(s):  
Samah Hashim Albayati ◽  
Malihe Masomian ◽  
Siti Nor Hasmah Ishak ◽  
Mohd Shukuri bin Mohamad Ali ◽  
Adam Leow Thean ◽  
...  
Keyword(s):  
Substrate Specificity ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Random Mutagenesis ◽  
Binding Pocket ◽  
Amino Acid Sequences ◽  
Site Directed Mutagenesis ◽  
Saturation Mutagenesis ◽  
Process Conditions

Microbial lipases represent one of the most important groups of biotechnological biocatalysts. However, the high-level production of lipases requires an understanding of the molecular mechanisms of gene expression, folding, and secretion processes. Stable, selective, and productive lipase is essential for modern chemical industries, as most lipases cannot work in different process conditions. However, the screening and isolation of a new lipase with desired and specific properties would be time consuming, and costly, so researchers typically modify an available lipase with a certain potential for minimizing cost. Improving enzyme properties is associated with altering the enzymatic structure by changing one or several amino acids in the protein sequence. This review detailed the main sources, classification, structural properties, and mutagenic approaches, such as rational design (site direct mutagenesis, iterative saturation mutagenesis) and direct evolution (error prone PCR, DNA shuffling), for achieving modification goals. Here, both techniques were reviewed, with different results for lipase engineering, with a particular focus on improving or changing lipase specificity. Changing the amino acid sequences of the binding pocket or lid region of the lipase led to remarkable enzyme substrate specificity and enantioselectivity improvement. Site-directed mutagenesis is one of the appropriate methods to alter the enzyme sequence, as compared to random mutagenesis, such as error-prone PCR. This contribution has summarized and evaluated several experimental studies on modifying the substrate specificity of lipases.

scholarly journals Potential Therapeutic Approaches to Alzheimer’s Disease By Bioinformatics, Cheminformatics And Predicted Adme-Tox Tools

2020 ◽  
Vol 18 (8) ◽  
pp. 696-719
Author(s):  
Speranta Avram ◽  
Maria Mernea ◽  
Carmen Limban ◽  
Florin Borcan ◽  
Carmen Chifiriuc
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmda Receptors ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Experimental Studies ◽  
Natural Compounds ◽  
Synthetic Compounds ◽  
Ache Inhibitors

Background: Alzheimer’s disease (AD) is considered a severe, irreversible and progressive neurodegenerative disorder. Currently, the pharmacological management of AD is based on a few clinically approved acethylcholinesterase (AChE) and N-methyl-D-aspartate (NMDA) receptor ligands, with unclear molecular mechanisms and severe side effects. Methods: Here, we reviewed the most recent bioinformatics, cheminformatics (SAR, drug design, molecular docking, friendly databases, ADME-Tox) and experimental data on relevant structurebiological activity relationships and molecular mechanisms of some natural and synthetic compounds with possible anti-AD effects (inhibitors of AChE, NMDA receptors, beta-secretase, amyloid beta (Aβ), redox metals) or acting on multiple AD targets at once. We considered: (i) in silico supported by experimental studies regarding the pharmacological potential of natural compounds as resveratrol, natural alkaloids, flavonoids isolated from various plants and donepezil, galantamine, rivastagmine and memantine derivatives, (ii) the most important pharmacokinetic descriptors of natural compounds in comparison with donepezil, memantine and galantamine. Results: In silico and experimental methods applied to synthetic compounds led to the identification of new AChE inhibitors, NMDA antagonists, multipotent hybrids targeting different AD processes and metal-organic compounds acting as Aβ inhibitors. Natural compounds appear as multipotent agents, acting on several AD pathways: cholinesterases, NMDA receptors, secretases or Aβ, but their efficiency in vivo and their correct dosage should be determined. Conclusion: Bioinformatics, cheminformatics and ADME-Tox methods can be very helpful in the quest for an effective anti-AD treatment, allowing the identification of novel drugs, enhancing the druggability of molecular targets and providing a deeper understanding of AD pathological mechanisms.

scholarly journals Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Marjan Talebi ◽  
Mohsen Talebi ◽  
Tahereh Farkhondeh ◽  
Jesus Simal-Gandara ◽  
Dalia M. Kopustinskiene ◽  
...  
Keyword(s):  
Blood Cells ◽  
Molecular Mechanisms ◽  
Web Of Science ◽  
Experimental Studies ◽  
Protective Effects ◽  
Pharmacological Activities ◽  
Current Review ◽  
Mesh Terms ◽  
Online Databases ◽  
Anti Cancer

AbstractChrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies. Graphic abstract

scholarly journals Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

2021 ◽  
Vol 22 (2) ◽  
pp. 660
Author(s):  
María Aguilar-Ballester ◽  
Gema Hurtado-Genovés ◽  
Alida Taberner-Cortés ◽  
Andrea Herrero-Cervera ◽  
Sergio Martínez-Hervás ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Leukocyte Adhesion ◽  
Experimental Studies ◽  
Lipid Lowering ◽  
Foam Cell Formation ◽  
Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

scholarly journals Herb-target virtual screening and network pharmacology for prediction of molecular mechanism of Danggui Beimu Kushen Wan for prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hong Li ◽  
Andrew Hung ◽  
Angela Wei Hong Yang
Keyword(s):  
Prostate Cancer ◽  
Binding Affinity ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Tight Binding ◽  
Experimental Studies ◽  
Network Pharmacology ◽  
High Morbidity ◽  
High Binding ◽  
High Binding Affinity

AbstractProstate cancer (PCa) is a cancer that occurs in the prostate with high morbidity and mortality. Danggui Beimu Kushen Wan (DBKW) is a classic formula for patients with difficult urination including PCa. This study aimed to investigate the molecular mechanisms of DBKW for PCa. We obtained DBKW compounds from our previous reviews. We identified potential targets for PCa from literature search, currently approved drugs and Open Targets database and filtered them by protein–protein interaction network analysis. We selected 26 targets to predict three cancer-related pathways. A total of 621 compounds were screened via molecular docking using PyRx and AutoDock Vina against 21 targets for PCa, producing 13041 docking results. The binding patterns and positions showed that a relatively small number of tight-binding compounds from DBKW were predicted to interact strongly and selectively with three targets. The top five high-binding-affinity compounds were selected to generate a network, indicating that compounds from all three herbs had high binding affinity against the 21 targets and may have potential biological activities with the targets. DBKW contains multi-targeting agents that could act on more than one pathway of PCa simultaneously. Further studies could focus on validating the computational results via experimental studies.

In silico and experimental studies of bovine serum albumin-encapsulated carbenoxolone nanoparticles with reduced cytotoxicity

2021 ◽  
pp. 111670
Author(s):  
Subhashini Bharathala ◽  
Lakshmi Kanth Kotarkonda ◽  
Vijay Pal Singh ◽  
Rajni Singh ◽  
Pankaj Sharma
Keyword(s):  
Bovine Serum Albumin ◽  
Serum Albumin ◽  
In Silico ◽  
Bovine Serum ◽  
Experimental Studies

scholarly journals Multidrug Antimicrobial Resistance and Molecular Detection of mcr-1 Gene in Salmonella Species Isolated from Chicken

Animals ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 206
Author(s):  
Md Bashir Uddin ◽  
S.M. Bayejed Hossain ◽  
Mahmudul Hasan ◽  
Mohammad Nurul Alam ◽  
Mita Debnath ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Antimicrobial Resistance ◽  
In Silico ◽  
Salmonella Enterica ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Genetic Relationships ◽  
Evolutionary Relationship ◽  
Salmonella Spp ◽  
Gram Negative

Colistin (polymyxin E) is widely used in animal and human medicine and is increasingly used as one of the last-resort antibiotics against Gram-negative bacilli. Due to the increased use of colistin in treating infections caused by multidrug-resistant Gram-negative bacteria, resistance to this antibiotic ought to be monitored. The study was undertaken to elucidate the molecular mechanisms, genetic relationships and phenotype correlations of colistin-resistant isolates. Here, we report the detection of the mcr-1 gene in chicken-associated Salmonella isolates in Bangladesh and its in-silico functional analysis. Out of 100 samples, 82 Salmonella spp. were isolated from chicken specimens (liver, intestine). Phenotypic disc diffusion and minimum inhibitory concentration (MIC) assay using different antimicrobial agents were performed. Salmonella isolates were characterized using PCR methods targeting genus-specific invA and mcr-1 genes with validation for the functional analysis. The majority of the tested Salmonella isolates were found resistant to colistin (92.68%), ciprofloxacin (73.17%), tigecycline (62.20%) and trimethoprim/sulfamethoxazole (60.98%). When screened using PCR, five out of ten Salmonella isolates were found to carry the mcr-1 gene. One isolate was confirmed for Salmonella enterica subsp. enterica serovar Enteritidis, and other four isolates were confirmed for Salmonella enterica subsp. enterica serovar Typhimurium. Sequencing and phylogenetic analysis revealed a divergent evolutionary relationship between the catalytic domain of Neisseria meningitidis lipooligosaccharide phosphoethanolamine transferase A (LptA) and MCR proteins, rendering them resistant to colistin. Three-dimensional homology structural analysis of MCR-1 proteins and molecular docking interactions suggested that MCR-1 and LptA share a similar substrate binding cavity, which could be validated for the functional analysis. The comprehensive molecular and in-silico analyses of the colistin resistance mcr-1 gene of Salmonella spp. of chicken origin in the present study highlight the importance of continued monitoring and surveillance for antimicrobial resistance among pathogens in food chain animals.

scholarly journals Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1840
Author(s):  
Camilo Febres-Molina ◽  
Jorge A. Aguilar-Pineda ◽  
Pamela L. Gamero-Begazo ◽  
Haruna L. Barazorda-Ccahuana ◽  
Diego E. Valencia ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Complex I ◽  
Binding Free Energy ◽  
Biological Activities ◽  
Experimental Studies ◽  
Respiratory Complex ◽  
Mitochondrial Respiratory Complex ◽  
Respiratory Complex I ◽  
Mitochondrial Respiratory

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.

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