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Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

ABSTRACT: Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 ?M to 50 ?M. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens.

SUBMITTER: Mogire RM

PROVIDER: S-EPMC5663372 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

Mogire Reagan M RM Akala Hoseah M HM Macharia Rosaline W RW Juma Dennis W DW Cheruiyot Agnes C AC Andagalu Ben B Brown Mathew L ML El-Shemy Hany A HA Nyanjom Steven G SG

PloS one 20171031 10

Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This ...[more]

PMID: 29088219

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Project description:BackgroundThe critically important issue on emergence of drug-resistant malarial parasites is compounded by cross resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action. This aspect requires discovery of new anti-malarial compounds or formulation of new combination therapy. The current study attempts to contribute towards accelerating anti-malarial drug development efforts, by exploring the potential of existing FDA-approved drugs to target proteins of Plasmodium falciparum.MethodsUsing comparative sequence and structure analyses, FDA-approved drugs, originally developed against other pathogens, were identified as potential repurpose-able candidates against P. falciparum. The rationale behind the undertaken approach is the likeliness of small molecules to bind to homologous targets. Such a study of evolutionary relationships between established targets and P. falciparum proteins aided in identification of approved drug candidates that can be explored for their anti-malarial potential.ResultsSeventy-one FDA-approved drugs were identified that could be repurposed against P. falciparum. A total of 89 potential targets were recognized, of which about 70 are known to participate in parasite housekeeping machinery, protein biosynthesis, metabolic pathways and cell growth and differentiation, which can be prioritized for chemotherapeutic interventions. An additional aspect of prioritization of predicted repurpose-able drugs has been explored on the basis of ability of the drugs to permeate cell membranes, i.e., lipophilicity, since the parasite resides within a parasitophorous vacuole, within the erythrocyte, during the blood stages of infection. Based on this consideration, 46 of 71 FDA-approved drugs have been identified as feasible repurpose-able candidates against P. falciparum, and form a first-line for laboratory investigations. At least five of the drugs identified in the current analysis correspond to existing antibacterial agents already under use as repurposed anti-malarial agents.ConclusionsThe drug-target associations predicted, primarily by taking advantage of evolutionary information, provide a valuable resource of attractive and feasible candidate drugs that can be readily taken through further stages of anti-malarial drug development pipeline.

Dataset Information

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

Publications

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

Similar Datasets

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