An integrated virtual screening and drug repurposing strategy for the discovery of new antimalarial drugs against Plasmodium falciparum phosphatidylinositol 3‐kinase

2021 ◽  
Author(s):  
Kanika Verma ◽  
Ayush K. Lahariya ◽  
Shivangee Dubey ◽  
Anil K. Verma ◽  
Aparup Das ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
Drug Repurposing ◽  
Antimalarial Drugs ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals IN-SILICO SCREENING AGAINST ANTIMALARIAL TARGET PLASMODIUM FALCIPARUM ENOYL-ACYL CARRIER PROTEIN REDUCTASE

2017 ◽  
Vol 10 (17) ◽  
pp. 127
Author(s):  
Berwi Fazri Pamudi ◽  
Azizahwati Azizahwati ◽  
Arry Yanuar
Keyword(s):  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
In Silico ◽  
Acyl Carrier Protein ◽  
Parasitic Infection ◽  
Antimalarial Drugs ◽  
Chemotherapeutic Agents ◽  
Effective Vaccine ◽  
Carrier Protein ◽  
In Silico Screening

  Objective: Malaria is a parasitic infection that causes worldwide health problems. The absence of an effective vaccine and Plasmodium strains that are resistant to antimalarial drugs emphasize the importance of developing new chemotherapeutic agents. The use of computers for in-silico screening, or virtual screening, is currently being developed as a method for discovering antimalarial drugs. One of the enzymes that can support the development of the malaria parasite is the Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR). Inhibition of these enzymes leads to Type II lipid biosynthesis inhibition on the parasite.Methods: This research investigates the use of virtual screening to find PfENR inhibitor candidates. A molecular docking method using GOLD software and the medicinal plants in Indonesia database will be used. This target has been optimized by the removal of residues and the addition of charge. Ligand is expected to be an inhibitor of PfENR.Results: In-silico screening, or virtual screening, found that the top five compounds with the highest GOLD score at trial are kaempferol 3-rhamnosyl- (1-3)-rhamnosyl-(1-6)-glucoside; cyanidin 3,5-di-(6-malonylglucoside); 8-hydroxyapigenin 8-(2’’, 4’’-disulfato glucuronide); epigallocatechin 3,5,-di- O-gallat; quercetin 3,4’-dimethyl ether 7-alpha-L-arabinofuranosyl-(1-6)-glucoside. They had GOLD scores of 94.73, 95.90, 86.46, 85.39, and 84.40, respectively.Conclusions: There are two candidate inhibitor compounds from tea (Camellia sinensis), which have potential for development as an antimalarial drug, which are kaempferol 3-rhamnosyl-(1-3)-rhamnosyl-(1-6)-glucoside and epigallocatechin 3,5,-di-O-gallate, with a GOLD score of 94.73 and 85.39, respectively.

scholarly journals PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking

Blood ◽  
2010 ◽  
Vol 115 (12) ◽  
pp. 2500-2507 ◽  
Author(s):  
Ankush Vaid ◽  
Ravikant Ranjan ◽  
Wynand A. Smythe ◽  
Heinrich C. Hoppe ◽  
Pushkar Sharma
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Second Messengers ◽  
Active Form ◽  
Food Vacuole ◽  
Parasite Growth ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Inhibitors ◽  
Parasite Plasmodium ◽  
Phosphatidylinositol 3

Abstract Polyphosphorylated phosphoinositides (PIPs) are potent second messengers, which trigger a wide variety of signaling and trafficking events in most eukaryotic cells. However, the role and metabolism of PIPs in malaria parasite Plasmodium have remained largely unexplored. Our present studies suggest that PfPI3K, a novel phosphatidylinositol-3-kinase (PI3K) in Plasmodium falciparum, is exported to the host erythrocyte by the parasite in an active form. PfPI3K is a versatile enzyme as it can generate various 3′-phosphorylated PIPs. In the parasite, PfPI3K was localized in vesicular compartments near the membrane and in its food vacuole. PI3K inhibitors wortmannin and LY294002 were effective against PfPI3K and were used to study PfPI3K function. We found that PfPI3K is involved in endocytosis from the host and trafficking of hemoglobin in the parasite. The inhibition of PfPI3K resulted in entrapment of hemoglobin in vesicles in the parasite cytoplasm, which prevented its transport to the food vacuole, the site of hemoglobin catabolism. As a result, hemoglobin digestion, which is a source of amino acids necessary for parasite growth, was attenuated and caused the inhibition of parasite growth.

Heterologous Expression, Purification, and Functional Analysis of Plasmodium falciparum Phosphatidylinositol 3′-Kinase

Biochemistry ◽  
2017 ◽  
Vol 56 (33) ◽  
pp. 4335-4345 ◽  
Author(s):  
Matthew R. Hassett ◽  
Anna R. Sternberg ◽  
Bryce E. Riegel ◽  
Craig J. Thomas ◽  
Paul D. Roepe
Keyword(s):  
Functional Analysis ◽  
Plasmodium Falciparum ◽  
Heterologous Expression ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals Identification of steroid-like natural products as antiplasmodial agents by 2D and 3D similarity-based virtual screening

MedChemComm ◽  
2017 ◽  
Vol 8 (6) ◽  
pp. 1152-1157 ◽  
Author(s):  
Elumalai Pavadai ◽  
Gurminder Kaur ◽  
Sergio Wittlin ◽  
Kelly Chibale
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Natural Products ◽  
Virtual Screening ◽  
Antimalarial Drugs ◽  
2D And 3D ◽  
3D Similarity

The emergence of drug resistance in Plasmodium falciparum to available antimalarial drugs has challenged current antimalarial treatments.

scholarly journals Expression of The Fab Enzymes (Fab I And Fab Z) From Plasmodium Falciparum After Exposure To Artemisia Afra Plant Extracts And Drugs Screening

2021 ◽  
Author(s):  
Ndeye Fatou Kane ◽  
Mutinda Cleophas Kyama ◽  
Joseph Kangethe Nganga ◽  
Ahmed Hassanali ◽  
Mouhamadou Diallo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
Plant Extracts ◽  
Malaria Parasite ◽  
Fatty Acid Biosynthesis ◽  
Expression Patterns ◽  
Ethanolic Extract ◽  
Antimalarial Drugs ◽  
Hexane Extracts ◽  
The Ideal

Abstract Background:The emergence and spread of drug resistance of the malaria parasite to the main treatment emphasis the need to develop new antimalarial drugs. In this context, the fatty acid biosynthesis (FAS_II) pathway of the malaria parasite is one of the ideal target due to its crucial role in parasite survival.Method:We report in this study the expression and the affinity binding of two Fab enzymes (FabI and FabZ) after exposure of the parasite using different extracts of the Artemisia afra and after a virtual screening with the different plant compounds. Two differents strains of Plasmodium falciparum was used: W2 (CQ_resistant) and D6 (CQ_sensitive) with a parasiteamia of 4%. The parasites were exposed during 2 days to different Artemisia afra extracts . Gene expression was done to determine the level of expression of the fab enzymes after treatments. A GCMS was run to determine the different compounds of the plant extracts following by a virtual screening between the fab enzymes and the active compounds using Pyrex. Result:The results showed different expression patterns of the Fab enzymes. FabI was downregulated in the W2 and D6 strains by the ethanolic extract in a higher rate for W2. Hexane and DCM extracts increased the production of FabI respectively in W2 and D6 strains. A different expression pattern was observed for Fab Z. The expression of FabZ in the W2 strain were all upregulated. The enzyme was downregulated only in the D6 strain when exposed to the ethanolic and hexane extracts of the plant. After virtual screening, a lot of compounds were found to interact with the two fab enzymes. Hits compounds for FabI and FabZ with high biding energy were detected. 11alpha-Hydroxyprogesterone and Aspidospermidin-17-ol were found to have high binding energy with FabI respectively (-10.7 kcal/mol; -10.2kcal/mol). Fab Z was having also a high affinity with the two following hits compounds: 11alpha-Hydroxyprogesterone (-10 kcal/mol) and Thiourea (-8.4 Kcal/mol). Conclusion:The study showed that Artemisia afra is a big source of antimalarial drugs, and could act not only as a curative but also as prophylactic due to its effects on the Fab enzymes.

Possibility of distinct insulin-signaling pathways beyond phosphatidylinositol 3-kinase-mediating glucose transport and lipogenesis

Diabetes ◽  
1998 ◽  
Vol 47 (2) ◽  
pp. 179-185 ◽  
Author(s):  
R. W. Stevenson ◽  
D. K. Kreutter ◽  
K. M. Andrews ◽  
P. E. Genereux ◽  
E. M. Gibbs
Keyword(s):  
Signaling Pathways ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3
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