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

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

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

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Distribution of the expected apicoplast targets according to their predicted metabolic function in the apicoplast.

<p>Distribution of the expected apicoplast targets according to their predicted metabolic function in the apicoplast.</p

New drug-target associations disclosed in the present study.

<p>(NA: not available; codes in brackets represent the target Identity Code of DrugBank. Toxicity data is cited from DrugBank; FAS: Fatty Acid Synthesis; LD50: drug dose that results in death of 50% of the animals).</p

Examples of drug-target associations previously determined, that were correctly identified in the present study.

<p>(codes in brackets represent the target Identity Code of DrugBank. In the cases of Fosmidomycin, Triclosan and Geldanamycin, there are no homologous targets represented because they were identified using STITCH3.1 which uses an algorithm where homologous targets are not displayed).</p

Flowchart summarizing the work pipeline and corresponding results.

<p>(*denotes the targets that were discarded on the basis of having chemical affinity to dietary supplements/nutraceuticals).</p