Search for New Antimalarial Compounds Obtained From Natural Sources by Molecular Modeling

Artemisinin is a sesquiterpene lactone with an endoperoxide function that is currently being used against strains of Plasmodium falciparum. Endoperoxides are supposed to act on heme leading to reduction of the peroxide bond and production of radicals that can kill the parasite. As artemisinin, other natural compounds have the peroxide group and may also show antimalarial activity. This fact motivated us to study the interaction of 18 peroxides natural Brazilian flora with the heme group and compared with the values obtained for artemisinin. Initially, a conformational search was performed using the MM3 method for each molecule. The most stable conformers were optimized by the PM3(tm) method. Then, there was a docking between the peroxide and the heme group, again followed by a conformational search. Finally, the complex was optimized to obtain highest occupied molecular orbital, lowest unoccupied molecular orbital, and molecular electrostatic potential (MEP) by the PM3(tm) method. All these calculations were performed using the Titan package. Among the natural peroxides, we studied (18), four have molecular orbital, MEP, and interaction energies similar to artemisinin. (C) 2010 Wiley Periodicals, Inc. Int J Quantum Chem 110: 2057-2066, 2010