Identifying multiple drug targets for heme detoxification by using plasmodium metabolism model in red blood cell

Abstract

Detoxification is an essential process in a living organism for removing toxic substances from the cell. In red ิblood cell cycle, Plasmodium falciparum, the most devastating malaria parasite, digests hemoglobin from blood and forms hemozoin to eliminate free heme which is toxic to the parasite. Therefore, the hemozoin formation is essential to the survival of the parasite and become an attractive target for developing drugs. Nowadays, computational approaches have been a great tool to reduce time and cost in drug development process. In this work, we reconstructed constraint-based metabolic model of P. falciparum and human red blood cell. To identify drug target we apply flux balance analysis to this model in two objectives. One is for pathological stage in human, another one is for medication stage. The reactions which its flux value are change to zero in medication stage are assumed to be preliminary potential targets due to inhibited by drug treatment. The number of preliminary potential targets were reduced by test all combination to search the best set of potential drug targets to inhibit heme detoxification in P. falciparum. Finally, we obtained heme ligase is one potential drug targets and combination with nitrite reductase[NAD(P)H] and inositol-3-phosphate synthase for optimal drug targets. In conclusion, this method shown an effective way to identify drug targets which is useful in drug development process.