scholarly journals Docking of New Designed Compounds Derived from 1,6-Dihydro-1,3,5-triazine-2,4-diamine Toward Quadruple Mutant Plasmodium Dihydrofolate Reductase

2019 ◽  
Vol 19 (3) ◽  
pp. 777
Author(s):  
Imam Siswanto ◽  
Harno Dwi Pranowo ◽  
Mudasir Mudasir
Keyword(s):  
Dihydrofolate Reductase ◽  
Antimalarial Activity ◽  
Interaction Model ◽  
Data Bank ◽  
Basis Set ◽  
Receptor Complex ◽  
Partial Charges ◽  
Quadruple Mutant ◽  
Complex Ligand ◽  
Better Than

Resistance to the traditional antifolates is now widespread in Plasmodium falciparum and Plasmodium vivax. To find the interaction model of some compounds derived from 1,6-dihydro-1,3,5-triazine-2,4-diamine, molecular docking technique was carried out using these compounds ligand and pDHFR as the receptor. Complex ligand and the receptor from Protein Data Bank (PDB ID 1J3K) were chosen as an interaction model between a ligand and its receptor. Each compound was optimized using ab initio methods with 6-311G basis set. Partial charges of ligand were added using AM1-BCC methods. Each ligand was docked to the receptor utilizing Dock6 software. Theoretical prediction based on the binding energy between these compounds as the ligand with pDHFR as receptor resulted in 1 compound, namely 6,6-dimethyl-1-[3-(2-chloro-4,5-dibromophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine possessing binding affinity better than that of WR99210 which was known to have good antimalarial activity.

scholarly journals In Silico Insight the Prediction of Chlorogenic Acid in Coffee through Cyclooxygenase-2 (COX2) Interaction

2019 ◽  
Vol 7 (2) ◽  
Author(s):  
Yohanes Bare ◽  
Dewi Ratih Tirto Sari ◽  
Yoga Tribakti Rachmad ◽  
Gabriella Candrakirana Krisnamurti ◽  
Agustina Elizabeth
Keyword(s):  
Chlorogenic Acid ◽  
Potential Role ◽  
Interaction Model ◽  
Data Bank ◽  
High Permeability ◽  
Discovery Studio ◽  
Docking Approach ◽  
Cox 2 ◽  
Therapeutic Compound

Inflammation was signs of pathological or abnormality in tissue to give an alert as a trouble signal to the system. Therapeutic using NSAIDs has some side effects. This research explored the potential role of chlorogenic acid as natural therapeutic compound to inhibit the inflammation target such as COX-2 by interaction model. The research method used in this study was the molecular docking approach, which binds ligand and protein. Protein data provided by Protein Data Bank (ID: 6cox) while, chlorogenic acid obtain from PubChem (CID: 1794427). We docked COX-2 and chlorogenic acid using Hex 8.0.0. Visualization and analysis of the molecular interactions of chlorogenic acid and COX-2 conducted by the Discovery Studio Client 4.1 software. Chlorogenic acid has a high permeability and is easily absorbed based on five Lipinski Rule. Interestingly, we found Fifteen amino acid was binding with chlorogenic acid that formed by hydrogen bond and van der Waals.The interaction between ligand-protein results in energy binding -327.59cal/mol. Chlorogenic acid has a potential role to inhibit inflammation pathway by inhibiting COX-2. We predicted chlorogenic acid has a potential as therapy anti-inflammatory to suppress COX-2 as mediator inflammation.

scholarly journals EFFECT OF INQUIRY TRAINING LEARNING MODEL DAN CREATIVITY ON SCIENCE PROCESS SKILLS

2016 ◽  
Vol 5 (1) ◽  
pp. 44 ◽  
Author(s):  
Purnama Silitonga ◽  
Mara Bangun Harahap ◽  
Derlina .
Keyword(s):  
Interaction Model ◽  
Sampling Technique ◽  
Learning Model ◽  
Process Skills ◽  
Learning Models ◽  
Science Process Skills ◽  
The Difference ◽  
Model Training ◽  
Cluster Random Sampling ◽  
Better Than

This study aims: 1) to determine differences in science process skills of students with learning model inquiry training and conventional learning models, 2) to determine the difference science process skills of students who have high creativity and creativity is low, 3) to determine the interaction model of learning inquiry trainingwith creativity of the science process skills. The sampling technique conducted cluster random sampling two classes, where first class as a class experiment with the number of students 32 people applied learning model inquiry training (X-1) and the second class as a class control the number of students 32 people who applied conventional learning model ( X-2). Instruments in this study is the science process skills test and a test of creativity in the form of a description. From these results it can be concluded that: 1) science process skills of students that learned with a learning model inquiry training is better than the students that learned with conventional learning models, 2)science process skills of students with high creativity better than students with creativity is low, 3) there is interaction between inquirylearning model training and creativity in influencing the science process skills of students.

Decreased susceptibility to dihydrofolate reductase inhibitors associated with genetic polymorphisms in Ugandan Plasmodium falciparum isolates

2021 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Patrick K Tumwebaze ◽  
Oswald Byaruhanga ◽  
Thomas Katairo ◽  
Martin Okitwi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Mixed Genotype ◽  
Susceptibility Data ◽  
Reductase Inhibitors ◽  
Excellent Activity ◽  
Quadruple Mutant ◽  
Dihydrofolate Reductase Inhibitors

Abstract Background The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug susceptibility data for P. falciparum field isolates are limited. Methods We studied ex vivo PfDHFR inhibitor susceptibilities of 559 isolates from Tororo and Busia districts, Uganda from 2016-2020, sequenced 383 isolates, and assessed associations between genotypes and drug susceptibility phenotypes. Results Median IC50’s were 42,100 nM for pyrimethamine, 1,200 nM for cycloguanil, 13,000 nM for proguanil, and 0.6 nM for P218. Among sequenced isolates, three PfDHFR mutations, 51I (100%), 59R (93.7%), and 108N (100%), were very common, as previously seen in Uganda, and another mutation, 164L (12.8%), had moderate prevalence. Increasing numbers of mutations were associated with decreasing susceptibility to pyrimethamine, cycloguanil, and P218, but not proguanil, which does not act directly against PfDHFR. Differences in P218 susceptibilities were modest, with median IC50 1.4 nM for parasites with mixed genotype at position 164 and 5.7 nM for pure quadruple mutant (51I/59R/108N/164L) parasites. Conclusion Resistance-mediating PfDHFR mutations were common in Ugandan isolates, but P218 retained excellent activity against mutant parasites.

Antimalaria Activity of Cassia spectabilis DC Leaf and Its Inhibition Effect in Heme Detoxification

2020 ◽  
Author(s):  
Wiwied - Ekasari ◽  
Dewi Resty Basuki ◽  
Heny - Arwati ◽  
Tutik Sri Wahy
Keyword(s):  
Antimalarial Activity ◽  
Ethanol Extract ◽  
Ic50 Value ◽  
Cassia Spectabilis ◽  
In Vivo Testing ◽  
Chloroquine Diphosphate ◽  
Better Than

Abstract Background In previous studies, Cassia spectabilis DC leaf has shown a good antimalarial activity. Therefore, this study is a follow-up study of leaf activity and mechanism of C. spectabilis DC as an antimalarial. Methods In vitro antimalarial activity testing using P. falciparum which was done with bioassay guide isolation in order to obtain the active compound. In vivo testing towards infected P. berghei mice was conducted to determine the effects of antimalarial prophylaxis and antimalarial activity in combination with artesunate. Whereas, heme detoxification inhibition testing as one of the antimalarial mechanisms was carried out using the Basilico method. Results The results showed that active antimalarial isolate obtained from C. spectabilis DC leaf had a structural pattern that was identical to (-)-7-hydroxyspectaline. Prophylactic test on infected P. berghei mice obtained the highest dose of inhibition percentage of 90% ethanol extract of C. spectabilis DC leaf was 68.61% while positive (doxycycline) control at 100 mg kg-1 was 73.54%. In antimalarial testing in combination with artesunate, it was found that administering 150 mg kg-1 (three times a day) of C. spectabilis DC (D0 − D2) + artesunate (D2) was better than the standard combination of amodiaquine + artesunate with 99.18% and 92.88% inhibition percentage. For the inhibitory activity of heme detoxification from ethanol extract 90%, C. spectabilis DC leaf had IC50 value of 0.375 mg mL-1 which was better than chloroquine diphosphate. Conclusion These results showed that C. spectabilis DC leaves possesses potent antimalarial activity and may offer a potential agent for effective and affordable antimalarial phytomedicine.

scholarly journals Antibacterial activities of epiroprim, a new dihydrofolate reductase inhibitor, alone and in combination with dapsone.

1996 ◽  
Vol 40 (6) ◽  
pp. 1376-1381 ◽  
Author(s):  
H H Locher ◽  
H Schlunegger ◽  
P G Hartman ◽  
P Angehrn ◽  
R L Then
Keyword(s):  
Dihydrofolate Reductase ◽  
Biological Fluids ◽  
Pneumocystis Carinii ◽  
Antibacterial Activities ◽  
Gram Negative Bacteria ◽  
Highly Active ◽  
Excellent Activity ◽  
Resistant Strains ◽  
Better Than

Epiroprim (EPM; Ro 11-8958) is a new selective inhibitor of microbial dihydrofolate reductase. EPM displayed excellent activity against staphylococci, enterococci, pneumococci, and streptococci which was considerably better than that of trimethoprim (TMP). EPM was also active against TMP-resistant strains, although the MICs were still relatively high. Its combination with dapsone (DDS) was synergistic and showed as in vitro activity superior to that of the TMP combination with sulfamethoxazole (SMZ). The EPM-DDS (ratio, 1:19) combination inhibited more than 90% of all important gram-positive pathogens at a concentration of 2 + 38 micrograms/ml. Only a few highly TMP-resistant staphylococci and enterococci were not inhibited. EPM was also more active than TMP against Moraxella catarrhalis, Neisseria meningitidis, and Bacteroides spp., but it was less active than TMP against all other gram-negative bacteria tested. Atypical mycobacteria were poorly susceptible to EPM, but the combination with DDS was synergistic and active at concentrations most probably achievable in biological fluids (MICs from 0.25 +/- 4.75 to 4 + 76 micrograms/ml). EPM and the EPM-DDS combination were also highly active against experimental staphylococcal infections in a mouse septicemia model. The combination EPM-DDS has previously been shown to exhibit activity in Pneumocystis carinii and Toxoplasma models and, as shown in the present study, also shows good activity against a broad range of bacteria including many strains resistant to TMP and TMP-SMZ.

scholarly journals BLASTing away preconceptions in crystallization trials

2019 ◽  
Vol 75 (3) ◽  
pp. 184-192 ◽  
Author(s):  
Gabriel Jan Abrahams ◽  
Janet Newman
Keyword(s):  
Protein Data Bank ◽  
Sequence Similarity ◽  
Three Dimensional ◽  
Protein Sequences ◽  
Protein Molecule ◽  
Data Bank ◽  
Dimensional Structure ◽  
Critical Step ◽  
Quantitative Verification ◽  
Better Than

Crystallization is in many cases a critical step for solving the three-dimensional structure of a protein molecule. Determining which set of chemicals to use in the initial screen is typically agnostic of the protein under investigation; however, crystallization efficiency could potentially be improved if this were not the case. Previous work has assumed that sequence similarity may provide useful information about appropriate crystallization cocktails; however, the authors are not aware of any quantitative verification of this assumption. This research investigates whether, given current information, one can detect any correlation between sequence similarity and crystallization cocktails. BLAST was used to quantitate the similarity between protein sequences in the Protein Data Bank, and this was compared with three estimations of the chemical similarities of the respective crystallization cocktails. No correlation was detected between proteins of similar (but not identical) sequence and their crystallization cocktails, suggesting that methods of determining screens based on this assumption are unlikely to result in screens that are better than those currently in use.

scholarly journals Pollen analysis: state of the art

2010 ◽  
Vol 31 (1-2) ◽  
pp. 151-159 ◽  
Author(s):  
Gordon J. Ogden
Keyword(s):  
North America ◽  
Pollen Analysis ◽  
Sediment Cores ◽  
Data Bank ◽  
Sedimentation Rates ◽  
Data Set ◽  
Radiocarbon Dates ◽  
Surface Pollen ◽  
Pollen Stratigraphy ◽  
Better Than

Although nearly 50 years have passed since P.B. Sears introduced pollen analysis to North America, it remains an occult art. Dramatic improvements in sampling and analytic techniques continue to be limited by intractable problems of differential production, dispersal, ballistics, sedimentation, and preservation. It is a basic tenet of pollen stratigraphy that the data set, consisting primarily of microfossils preserved in sediments, is better than anything we have yet been able to do with it. Basic agreement between late- and postglacial pollen records has been confirmed wherever the method has been applied. Quantitative sampling techniques, sample preparation, and analytic procedures, together with multiple radiocarbon dates, permits calculation of sedimentation rates and absolute pollen influx. Of approximately 300 sediment cores from northeastern North America, fewer than 30 have more than 3 radiocarbon determinations from which least squares power curve regressions can be reliably calculated in the determination of sedimentation rates. Analogy with modern environments represented by surface pollen spectra is limited by an insufficient number of samples of uniform quality to characterize a vegetational mosaic covering 40 degrees of latitude (40-80°N) and longitude (60-100°W). The present surface pollen data bank includes about 700 samples, unevenly spaced and of uneven quality, permitting a grid resolution of no better than 10,000 km2.

scholarly journals In Vitro Activities of Several Diaminomethylpyridopyrimidines against Mycobacterium avium Complex

1998 ◽  
Vol 42 (12) ◽  
pp. 3315-3316 ◽  
Author(s):  
Carolyn M. Shoen ◽  
Olga Choromanska ◽  
Robert C. Reynolds ◽  
James R. Piper ◽  
Cheryl A. Johnson ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Mycobacterium Avium ◽  
Mycobacterium Avium Complex ◽  
Dhfr Inhibitors ◽  
Better Than

ABSTRACT Three recently synthesized dihydrofolate reductase (DHFR) inhibitors designated SoRI 8890, 8895, and 8897 were evaluated for their in vitro activities against 25 isolates of Mycobacterium avium complex. The MICs at which 50 and 90% of isolates were inhibited were 1 and 2, 4 and 8, and 4 and 8 μg/ml for SoRI 8890, 8895, and 8897, respectively. Although the addition of dapsone at 0.5 μg/ml did not significantly enhance the in vitro activities of these compounds, their activities alone were comparable to, if not better than, results seen with other DHFR inhibitors, such as pyrimethamine or WR99210.

scholarly journals SVECV-F12: A Composite Scheme for an Accurate and Cost Effective Evaluation of Reaction Barriers. I. Benchmarking Using the HTBH38/08 and NHTBH38/08 Barrier Heights Databases

2020 ◽  
Author(s):  
Oscar Ventura
Keyword(s):  
Density Functional ◽  
Cost Effective ◽  
Basis Set ◽  
Barrier Heights ◽  
Composite Methods ◽  
Complete Basis Set ◽  
Complete Basis Set Limit ◽  
Complete Set ◽  
Reaction Barriers ◽  
Better Than

A simple version of a composite scheme is described, based on a combination of density functional geometry and frequencies evaluation, valence energies obtained using the CCSD(T)-f12 method extrapolated to the complete basis set limit, and core-valence correlation corrections employing the MP2 method. The procedure was applied to the 38 reactions in Truhlar’s HTBH38/08 and NHTBH38/08 databases. Mean unsigned deviation (MUD) for the complete set of 68 independent barriers is 0.43 kcal mol-1, compared to 1.37 kcal/mol for G4 and 1.69 kcal/mol for the dispersioncorrected M06-2X method. Its accuracy is also better that that of other calculations using composite methods of similar cost. The MUD of the new scheme on the barriers in the DBH24/08 subset (12 out of the 38 reactions in both other sets) is 0.31 kcal mol-1, better than that obtained at the expensive CCSD(T,full)/aug-cc-pCV(T+d)Z level (0.46 kcal mol-1) and comparable to the most exact (and costly) Wn calculations (MUD=0.14 kcal mol-1). The maximum unsigned deviation (MaxUD) of the new method for all the reactions studied is 1.71 kcal/mol. G4 and M06-2X, on the other side, exhibit MaxUDs of 6.7 and 8.4 kcal/mol respectively

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