In silico repositioning using target-similarity search identifies approved drugs that have in vitro antimalarial activity against Plasmodium falciparum

Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for treatment of malaria. Search for new chemical entities often fail at safety and toxicity stages of drug development. Drug repositioning offers an alternative strategy where drugs that have already been approved for other diseases and conditions are used to treat malaria and other diseases. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in-vitro verification. All the Plasmodium falciparum proteins sequences available at NCBI RefSeq were used to perform a similarity search between these proteins and putative target proteins of approved drugs in Therapeutic Target Database, DrugBank and STITCH 4.0 databases. Druggability indices of the potential drug targets were obtained from TDR targets database. Functional residues of the drug targets were determined using ConSurf server which were used to fine tune the similarity search. A literature search at PubMed and Google Scholar identified drugs that have been previously been tested against malaria, these were excluded from further analysis. Finally, drug susceptibility assays using SYBR Green method was done to validate the antimalarial activity of the untested drugs. This study predicted 133 approved drugs could target 28 P. falciparum proteins. Published literature showed 99 of these drugs have been tested against malaria, most of which have antimalarial activity. A representative group of 10 of the 34 untested drugs were screened using in vitro drugs susceptibility tests. 8 out of the 10 showed antimalarial activity with IC 50 values below 50,000 ng/ml. These results show that target similarity can been used to correctly identify approved drugs with antimalarial activity, validating it as a viable method for repositioning drugs for antimalarial use.