scholarly journals Analgesic activity of Alpinia galanga extract in mice models and TNF-alpha receptor computational docking analysis on its leads with pharmacokinetics prediction

2018 ◽  
Vol 7 (3) ◽  
pp. 446 ◽  
Author(s):  
K. R. Subash ◽  
G. Francis Britto ◽  
Katari Sudheer Kumar ◽  
Amineni Umamaheshwari ◽  
Vijaya Chandra Reddy Konda ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Chemical Structure ◽  
Computational Analysis ◽  
Binding Free Energy ◽  
Ethanolic Extract ◽  
Standard Group ◽  
Lead Compound ◽  
Mice Model ◽  
Computational Docking ◽  
Alpinia Galanga

Background: Alpinia galanga is an ayurvedic herb recognized and used across many traditional medicine systems for its analgesic and anti-inflammatory activity. The present study scientifically validates the potential anti nociceptive action of ethanolic extract of Alpinia galanga by chemical, neurogenic and inflammatory nociception model in mice followed by identification of potential lead compound by computational analysis.Methods: The assessment of anti nociceptive action is evaluated by Acetic acid induced abdominal constrictions and Formalin assay on ethonolic extract of Alpinia galanga, followed by 20 compounds with known chemical structure of Alpinia galanga is subjected to computational analysis to predict possible lead compound with desirable pharmacokinetic and drug like features.Results: The percentage inhibition rate of Aspirin (100mg/kg) was 82.15% compared to Alpinia galanga (100mg/kg) 19.63%, (200mg/kg) 33.02% and (400mg/kg) 57.13% by acetic acid induced abdominal constrictions antinociceptive mice model. Alpinia galanga 400mg/kg (71.70%) had comparable percentage inhibition of nociception to standard group indomethacin (88.71%) in formalin induced nociceptive mice model. Among 20 compounds screened for pharmacokinetic and drug like features, Galanal B had the binding free energy -56.664 when compared to control compound 2AZ5-56.000.Conclusions: The Alpinia galanga extract had significant anti nociceptive activity and followed by computational analysis of 20 compounds with known chemical structure predicted Galanal B as lead compound with best insilico pharmacokinetic and drug like features.

Automated, Accurate, and Scalable Relative Protein-Ligand Binding Free Energy Calculations using Lambda Dynamics

2020 ◽  
Author(s):  
E. Prabhu Raman ◽  
Thomas J. Paul ◽  
Ryan L. Hayes ◽  
Charles L. Brooks III
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Computational Cost ◽  
Combinatorial Libraries ◽  
Free Energy Calculations ◽  
Lead Optimization ◽  
Efficient Estimation ◽  
Lead Compound

<p>Accurate predictions of changes to protein-ligand binding affinity in response to chemical modifications are of utility in small molecule lead optimization. Relative free energy perturbation (FEP) approaches are one of the most widely utilized for this goal, but involve significant computational cost, thus limiting their application to small sets of compounds. Lambda dynamics, also rigorously based on the principles of statistical mechanics, provides a more efficient alternative. In this paper, we describe the development of a workflow to setup, execute, and analyze Multi-Site Lambda Dynamics (MSLD) calculations run on GPUs with CHARMm implemented in BIOVIA Discovery Studio and Pipeline Pilot. The workflow establishes a framework for setting up simulation systems for exploratory screening of modifications to a lead compound, enabling the calculation of relative binding affinities of combinatorial libraries. To validate the workflow, a diverse dataset of congeneric ligands for seven proteins with experimental binding affinity data is examined. A protocol to automatically tailor fit biasing potentials iteratively to flatten the free energy landscape of any MSLD system is developed that enhances sampling and allows for efficient estimation of free energy differences. The protocol is first validated on a large number of ligand subsets that model diverse substituents, which shows accurate and reliable performance. The scalability of the workflow is also tested to screen more than a hundred ligands modeled in a single system, which also resulted in accurate predictions. With a cumulative sampling time of 150ns or less, the method results in average unsigned errors of under 1 kcal/mol in most cases for both small and large combinatorial libraries. For the multi-site systems examined, the method is estimated to be more than an order of magnitude more efficient than contemporary FEP applications. The results thus demonstrate the utility of the presented MSLD workflow to efficiently screen combinatorial libraries and explore chemical space around a lead compound, and thus are of utility in lead optimization.</p>

scholarly journals Inhibition study of proinflammatory factor with ethanolic extract of propolis on innate immunity from diabetes mellitus mice model

2018 ◽  
Vol 90 (2) ◽  
Author(s):  
Bambang Pristiwanto ◽  
Sutiman B. Sumitro ◽  
Muhammad S. Djati ◽  
Aris Soewondo ◽  
Hideo Tsuboi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Innate Immunity ◽  
Body Weight ◽  
Metabolic Diseases ◽  
Ethanolic Extract ◽  
Control Group ◽  
Mice Model ◽  
Innate Immunity Cells ◽  
Proinflammatory Factor ◽  
Ethanolic Extract Of Propolis

Health becomes an important topic today. One current problem was how to treat the effects of metabolic diseases, such as diabetes mellitus (DM). Thus, this study used an ethanolic extract of propolis (EEP), to test their ability as the supplement in the diabetes treatment to reduce inflammation, through proinflammatory factor response, especially nuclear factor κB (NF-κB). The streptozotocin- induced diabetes mellitus (SID) mice model was used, and expression of an proinflammatory factor was analyzed in their innate immunity cells with 3 doses of EEP, i.e. 50 mg/kg body weight, 100 mg/kg body weight, and 200 mg/kg body weight. Treatment of EEP in SID with three doses treatment decrease the number of macrophages with NF-κB expression significantly with DM control group. The results of B cells with NF-κB expression showed that EEP treatment in SID could decrease in dose 1 and dose 3, but not in dose 2. Proinflammatory cytokines expression of macrophage, especially Tumor Necrosis Factor-α and Interferon-γ, with EEP treatment in SID could decrease in three doses. This study suggests that EEP could reduce inflammation by inhibiting the development of NF-κB in innate immunity cells.

scholarly journals Comparative evaluation of anti-diabetic action and pancreatic histopathology of rats treated with two alkaloidal plant extracts

2020 ◽  
Vol 11 (SPL4) ◽  
pp. 1841-1846
Author(s):  
Bonagiri Sreedevi ◽  
Vijaya Kuchana ◽  
Shobharani S
Keyword(s):  
Blood Glucose ◽  
Ethanolic Extract ◽  
Bark Extract ◽  
Albino Rats ◽  
Histopathological Study ◽  
Standard Group ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Soxhlet Apparatus ◽  
Ethanolic Extracts

This study aimed to understand Strychnosnuxvomica and Holarrhena pubescens Stem bark extract action towards M3 receptor in controlling blood glucose levels. Strychnos nux vomica  and Holarrhena pubescens are both alkaloidal drugs can help in controlling Hyperglycemic level. This will be useful in the formulation of a new herbal drug molecule for treating diabetes. Chloroform and ethanolic extracts of selected alkaloidal plants were extracted using the soxhlet apparatus and obtained quotes were tested for acute toxicity studies and carried out anti-diabetic action on Wister albino rats for 21 days. Results obtained from Blood glucose levels and histopathological study of test groups are compared with blood glucose levels of standard group, and highly significant action was identified by the chloroform extract of Strychnos nux vomica and Holarrhena pubescens group. Moderate anti-diabetic action was observed remaining two groups of ethanolic extracts. Strychnos nux vomica and Holarrhena pubescens ethanolic extract groups are acting on M3 receptors and controlling Hyperglycemic levels.

Computational analysis of hereditary spastic paraplegia mutations in the kinesin motor domains of KIF1A and KIF5A

2020 ◽  
Vol 19 (06) ◽  
pp. 2041003
Author(s):  
Vidhyanand Mahase ◽  
Adebiyi Sobitan ◽  
Christina Johnson ◽  
Farion Cooper ◽  
Yixin Xie ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Stability ◽  
Molecular Motors ◽  
Intracellular Transport ◽  
Computational Analysis ◽  
Binding Free Energy ◽  
Membrane Vesicles ◽  
Energy Calculation ◽  
Missense Mutations ◽  
Kinesin Motor

Hereditary spastic paraplegias (HSPs) are a genetically heterogeneous collection of neurodegenerative disorders categorized by progressive lower-limb spasticity and frailty. The complex HSP forms are characterized by various neurological features including progressive spastic weakness, urinary sphincter dysfunction, extra pyramidal signs and intellectual disability (ID). The kinesin superfamily proteins (KIFs) are microtubule-dependent molecular motors involved in intracellular transport. Kinesins directionally transport membrane vesicles, protein complexes, and mRNAs along neurites, thus playing important roles in neuronal development and function. Recent genetic studies have identified kinesin mutations in patients with HSPs. In this study, we used the computational approaches to investigate the 40 missense mutations associated with HSP and ID in KIF1A and KIF5A. We performed homology modeling to construct the structures of kinesin–microtubule binding domain and kinesin–tubulin complex. We applied structure-based energy calculation methods to determine the effects of missense mutations on protein stability and protein–protein interaction. The results revealed that the most of disease-causing mutations could change the folding free energy of kinesin motor domain and the binding free energy of kinesin–tubulin complex. We found that E253K associated with ID in KIF1A decrease the protein stability of kinesin motor domains. We showed that the HSP mutations located in kinesin–tubulin complex interface, such as K253N and R280C in KIF5A, can destabilize the kinesin–tubulin complex. The computational analysis provides useful information for understanding the roles of kinesin mutations in the development of ID and HSPs.

scholarly journals Antidiabetic and Analgesic Effects of Glycosmis pentaphylla (Retz.) in Swiss Albino Mice

2013 ◽  
Vol 6 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Most. Chand Sultana Khatun ◽  
M Ripon Mia ◽  
M Ashraf Ali ◽  
M Moshiur Rahman ◽  
Khadiza Begum ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Analgesic Effect ◽  
Diclofenac Sodium ◽  
Methyl Cellulose ◽  
Ethanolic Extract ◽  
Oral Glucose ◽  
Standard Group ◽  
Antihyperglycemic Effect ◽  
Analgesic Effects ◽  
Dose Dependent

Background and purposes: Glycosmis pentaphylla (Retz.) Correa, a medicinal plant is popularly used as herbal remedy for various ailments in Bangladesh. It was also reported that GP has both anti-hyperglycemic and analgesic effects and being widely used to reduce blood glucose and to alleviate pain for many years in this region though published literatures are scarce. The present study was designed to evaluate whether ethanolic extract of Glycosmis pentaphylla (GP) have antihyperglycemic and analgesic effects. A total of 60 Swiss Albino male mice of nine weeks (weight, 20-25g) were used for investigation. Of them, 40 were made diabetic by alloxan. They were investigated in two groups – a) 20 mice by oral glucose tolerance test (4 samples OGTT) – at 0, 30, 90 and 120 min; and b) 20 mice for a week-long antihyperglycemic activity on day 0, 1, 3 & 7. Both the groups were subdivided into four, each having 5 mice – i) the ‘control’ received only 0.5% methyl cellulose as vehicle; ii) ‘Standard’ received vehicle plus metformin; iii & iv) test ‘DGP250’ & ‘DGP500’ received vehicle plus GP extract with 250 & 500 mg /kg, respectively. For the analgesic activity, 20 mice were investigated in four subgroups, each having 5 mice and similar steps were adopted. Here, vehicle was used 1% Tween 80 and intra-peritoneal injection of Acetic acid for eliciting pain in all four subgroups. The ‘standard’ group got diclofenac sodium for comparison with the test groups ‘GP250’ and ‘GP500’. In OGTT, Ethanolic extract of GP250 and GP500 reduced blood glucose at 90 min. But the levels of reduction were more significant at 120 min, 50.7% by GP250 and 66% by GP500 (p<0.001). The reduction is almost comparable with that induced by metformin. Likewise, for a weeklong anti-hyperglycemic activity, the GP extracts were found as equally effective as metfomin, which was also dose dependent. In addition to antihyperglycemic effect, the ethanolic extract of GP showed significant analgesic effect that was also dose dependent. Our results indicate that GP extract has antihyperglycemic effect in both short and in weeklong duration, which is almost comparable to Metformin HCL, a known and widely used antihyperglycemic agent. The GP extract was also found to have an analgesic effect almost comparable to diclofenac sodium, a known analgesic drug. Further study is needed to confirm the anti-hyperglycemic and analgesic effect of GP including its side effects in long term use. DOI: http://dx.doi.org/10.3329/imcj.v6i1.14721 Ibrahim Med. Coll. J. 2012; 6(1): 21-26

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