Identification of Potent Inhibitors of Drug-Sensitive and Drug-Resistant Plasmodium Falciparum
Uday Ck, Shaik Mahmood · 2010
Summary Malaria is a disease that causes more than 1 million deaths per year worldwide and more than 400 million clinical cases. Due to the acquired resistance of Plasmodium falciparum to the drugs used to control the infection, searching for new anti-malaria drugs is necessary in modern days. Recent studies have shown that the parasite synthesizes fatty acids using a fatty acid synthase type II (FAS-II) instead of a type-I fatty acid synthase (FAS-I) that is present in other eukaryotes. Plasmodium falciparum enoyl reductase (PfENR) is responsible for the last step of fatty acid biosynthesis in the parasite. This enzyme is located within the apicoplast, a plastid-like organelle that is responsible for several important metabolic pathways, including fatty acid biosynthesis. It is known that triclosan is an inhibitor of ENR in bacteria and we and others have shown that it is also effective against ENR in apicomplexan organisms such as P. falciparum. Three dimensional pharmacophore model was developed based on available P. falciparum enoyl acyl carrier protein (ACP) reductase inhibitors which were carefully selected with great diversity in both molecular structure and bioactivity as required by Hypo Gen program in the catalyst software in Discovery studio 2.5, Accelrys product for discovering new Pf EACP reductase inhibitors. Out of 41 molecules, 18 were taken as training set and remaining 23 were used for test set validation. The common feature pharmacophore or hip-hop consisted of four features namely two hydrogen bond acceptors, one hydrophobic and one hydrophobic aromatic. The best hypothesis of hypogen run consisting of four features namely two hydrogen bond acceptors and two hydrophobic, has a correlation coefficient of 0.958, a root mean square deviation of 1.044 and a cost difference of 93.241, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of 23 known Pf EACP reductase inhibitors in our test set with a correlation coefficient of 0.752(r). Accordingly, our model should be reliable in identifying structurally diverse compounds with desired biological activity. The next part of the study involved docking of two highly active and two low active Pf EACP reductase inhibitors against the Pf EACP reductase crystal protein using CDocker docking protocol available in Discovery studio2.5. The CDocker energies of two highly active inhibitors were -34.893 and -22.831 while that of one moderately active and one low active inhibitor were 21.447 and -19.847 respectively. All of the above four molecules showed interactions with the receptor mostly at Lys285 and Ser317 residues which are also existing among the crystal ligand interactions. Both from pharmacophore studies and from docking studies the results have shown that Triclosan and 2’ substituted Triclosan derivatives were high active inhibitors.