A Systematic In Silico Search for Target Similarity Identifies Several Approved Drugs with Potential Activity against the Plasmodium falciparum Apicoplast

Nadlla Alves Bispo,Richard Culleton,Pedro Cravo,Lourival Almeida Silva,Fabio T M Costa

doi:10.1371/journal.pone.0059288

Nadlla Alves Bispo, Richard Culleton + Show 3 more

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https://doi.org/10.1371/journal.pone.0059288

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Abstract

Most of the drugs in use against Plasmodium falciparum share similar modes of action and, consequently, there is a need to identify alternative potential drug targets. Here, we focus on the apicoplast, a malarial plastid-like organelle of algal source which evolved through secondary endosymbiosis. We undertake a systematic in silico target-based identification approach for detecting drugs already approved for clinical use in humans that may be able to interfere with the P. falciparum apicoplast. The P. falciparum genome database GeneDB was used to compile a list of ≈600 proteins containing apicoplast signal peptides. Each of these proteins was treated as a potential drug target and its predicted sequence was used to interrogate three different freely available databases (Therapeutic Target Database, DrugBank and STITCH3.1) that provide synoptic data on drugs and their primary or putative drug targets. We were able to identify several drugs that are expected to interact with forty-seven (47) peptides predicted to be involved in the biology of the P. falciparum apicoplast. Fifteen (15) of these putative targets are predicted to have affinity to drugs that are already approved for clinical use but have never been evaluated against malaria parasites. We suggest that some of these drugs should be experimentally tested and/or serve as leads for engineering new antimalarials.

Highlights

Malaria remains a serious public health problem in many tropical countries [1]
The main antimalarials presently approved for clinical use act mainly on two parasite metabolic pathways: haemoglobin degradation and nucleic acid synthesis
A list of a total 595 candidate target protein sequences was compiled and each was subsequently allocated either of the following predicted metabolic functions: ‘‘Replication, Transcription and Nucleic acid metabolism’’, ‘‘Translation’’, ‘‘Fatty acid and Phospholipid Metabolism’’, ‘‘Transport’’, ‘‘Antioxidant’’, ‘‘Protein Folding’’, ‘‘Fe-S Cluster Production’’, ‘‘Porphyrin Biosynthesis’’, ‘‘Post-translational Modification and Proteolysis’’ and ‘‘Other/unknown function’’ (Table S1). Each of these protein sequences in the list was interrogated for target similarity in the three databases used (DrugBank, STITCH3.1 and Target Database (TTD)), producing a list of a total seventy-two (72) ‘‘positive hits’’ (

Summary

Introduction

As there is still no effective vaccine available, treatment and prevention of the disease is primarily based on antimalarial drug administration and anti-vector measures, respectively. The efficacy of antimalarial drug treatment is compromised by the malaria parasite’s ability to develop drugresistance, and by the dearth of new and effective antimalarials in the drug-design pipeline. The main antimalarials presently approved for clinical use act mainly on two parasite metabolic pathways: haemoglobin degradation and nucleic acid synthesis. With the exception of artemisinin derivatives, parasite resistance has evolved and become common for the currently used antimalarial drugs. Resistance to drugs that block parasite nucleic acid synthesis, such as sulfadoxine, pyrimethamine and proguanil, is largely conferred by point mutations in genes encoding two enzymes, dihydrofolate reductase (DHFR) and the dihydropteroate synthase (DHPS) [3]

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