A proteomic glimpse into the effect of antimalarial drugs on Plasmodium falciparum proteome towards highlighting possible therapeutic targets

Abstract There is no effective vaccine against malaria; therefore, chemotherapy is to date only choice to fight against this infectious disease. However, there are growing evidences of drug-resistance mechanisms in malaria treatments. Therefore, the identification of new drug targets is an urgent need for the clinic management of the disease. Proteomic approaches offer the chance of determining the effects of antimalarial drugs on the proteome of Plasmodium parasites. Accordingly, we here review the effects of antimalarial drugs on Plasmodium falciparum proteome pointing out the relevance of several proteins as possible drug targets in malaria treatment. In addition, some of the P. falciparum stage-specific altered proteins and parasite-host interactions might play important roles in pathogenicity, survival, invasion, and metabolic pathways and thus serve as potential source of drug targets. In this review, we have identified several proteins including thioredoxin reductase, helicases, peptidyl-prolyl cis-trans isomerase, endoplasmic reticulum-resident calcium-binding protein, choline/ethanolamine phosphotransferase, purine nucleoside phosphorylase, apical membrane antigen 1, glutamate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase, heat shock protein70x, knob-associated histidine-rich protein, and erythrocyte membrane protein 1 as promising antimalarial drugs targets. Overall, proteomic approaches are able to partially facilitate finding the possible drug targets. However, the integration of other ‘omics’ and specific pharmaceutical techniques with proteomics may increase the therapeutic properties of the critical proteins identified in P. falciparum proteome.

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

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10s5.23114 ◽

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.

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Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics

10.1101/139386 ◽

2017 ◽

Cited By ~ 1

Author(s):

Annie N. Cowell ◽

Eva S. Istvan ◽

Amanda K. Lukens ◽

Maria G. Gomez-Lorenzo ◽

Manu Vanaerschot ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Multidrug Resistance ◽

Resistance Genes ◽

Genome Analysis ◽

Drug Targets ◽

Malaria Parasite ◽

Resistance Mechanisms ◽

Whole Genome

AbstractChemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence SummaryWhole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.

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Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum

Chemical Biology & Drug Design ◽

10.1111/j.1747-0285.2012.01389.x ◽

2012 ◽

Vol 80 (2) ◽

pp. 155-172 ◽

Cited By ~ 11

Author(s):

Tabish Qidwai ◽

Feroz Khan

Keyword(s):

Plasmodium Falciparum ◽

Fatty Acid ◽

Metabolic Pathway ◽

Drug Targets ◽

Antimalarial Drugs

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Important Docking study of Structure of Plasmodium falciparum thioredoxin reductase-thioredoxin complex: the case of potent drug Telatinib, a small molecule angiogenesis inhibitor

10.1101/2021.07.24.453649 ◽

2021 ◽

Author(s):

Ivan Vito Ferrari

Keyword(s):

Plasmodium Falciparum ◽

Tyrosine Kinases ◽

Drug Targets ◽

Redox Homeostasis ◽

Angiogenesis Inhibitor ◽

Thioredoxin Reductase ◽

Docking Study ◽

Autodock Vina ◽

Potent Drug ◽

Novel Drug

Background: Over the last decades, malaria parasites have been rapidly developing resistance against antimalarial drugs, which underlines the need for novel drug targets. Thioredoxin reductase (TrxR) is crucially involved in redox homeostasis and essential for Plasmodium falciparum. In this communication, we report first time important Docking study by in Silico approach, using AutoDock Vina. After a selective analysis of over 300 drugs, processed with Pyrx (a Virtual Screening software into the active site of protein (ID PDB 4J56 Thioredoxin reductase 2 Chain A), we noticed excellent value of Binding Energy of Telatinib estimated by Pyrx software. These results are comparable to the crystallized ligand FAD (FLAVIN-ADENINE DINUCLEOTIDE) completed in the above-mentioned protein. Indeed, from the results of Autodock Vina, Telatinib an inhibitor of tyrosine kinases, has excellent a Binding affinity value, ca. -12 kcal/mol.

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