Identification of approved drugs that have activity against Plasmodium falciparum using in silico and in vitro approaches

Abstract

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 are used to treat diseases or conditions other than the ones they have been approved for. This study screened approved drugs for antiplasmodial activity using an in silico chemogenomics approach prior to in vitro validation. All the P. falciparum protein sequences available at NCBI RefSeq were used to perform a similarity search between these proteins and putative target proteins of approved drugs in three databases: Therapeutic Target Database, DrugBank and STITCH. Functional residues of the drug targets were determined using ConSurf server which were used to fine tune the similarity search. Druggability indices of the potential drug targets were obtained from TDR targets database. A literature search was done to determine drugs previously been tested against malaria. Finally, drug susceptibility assays was done to validate the antimalarial activity of some of the predicted drugs. This study predicted 133 approved drugs that could target 28 P. falciparum proteins. Published literature search showed 99 of these drugs to have been tested against malaria, most of which had antiplasmodial activity. In vitro results showed 10 out of the 12 drugs tested had antiplasmodial activity with IC50 values below 100 μM on P. falciparum 3D7, these are Cladribine, Levofloxacin, Dasatinib, Clofarabine, Tacrolimus, Irinotecan, Zidovudine, Moxifloxacin, Oxaliplatin and Tadafil. Diadzin and Zafirlukast did not show any activity at concentration below 50,000 ng/ml. These results show that target similarity can be successfully used to identify approved drugs with antiplasmodial activity, validating it as a viable method for repositioning drugs for antimalarial use. The drugs that showed activity can further be analyzed for in vivo activity on rodents and also act as templates for synthesis of novel antimalarial drugs.