Tans-Atovaquone

Tans- atovaquone is widely used as an effective drug to treat uncomplicated malaria. But its cis-isomer is not a drug. In the present study, we report energy minimized binding pictures of trans-atovaquone and its cis- isomer from molecular docking studies of these drug molecules placed in Q0 site of cytochrome bc1(cytbc1) of yeast. The new feature of this computation is that structural parameters of the drug molecules have been obtained from their crystal structures. The energy minimized structure of protein-drug complex shows that H bond distant between His-181 of cytochrome bc1 and C=O of atovaquone for trans- atovaquone is 2.85 Å and 5.3 Å with the cis-isomer. The role of this H bonding interaction in dictating drug potency is in conformity

1998) are still used in the prevention and treatment of malaria. This class of drug acts (Banerjee R et al. 2002; Egan T.J. et al. 1994 and Slater A F G et al. 1992) on the food vacuoles of the parasites. Parasites obtain amino acids for protein translation and formation of their cell membrane from digestion of hemoglobin in the host. The undigested free toxic heme groups form reactive oxygen species. The natural process to remove toxic heme group from the parasitic cell is by the bio crystallization of heme to haemozoin (Pandey AV et al. 2003). The chloro-quinine inhibits this process of removal of toxic heme groups from parasitic cells and thus kills

1998) of the parasitic cells. The quinine group of ubiquone gets reduced to the quinol and helps in transferring the electron through an oxidation reduction cycle (Tielens A G M and Hellemond J J V 1998; Kroger A. and Gwith M K 1973). Atovaquone too has a quinine group and thus, it can mimic ubiquone and binds selectively to the Q0 site of parasitic mitochondria thereby block the parasitic mitochondrial respiration (Ridley R G 2002). In the present study, we report binding characteristics of trans and cis-isomers of atovaquone with cytochrome bc1 of yeast using docking technique in order to address the basic question, why trans isomer of atovaquone has much higher drug potency than that of its cis isomer? Recently, Hunte et al reported ( Hunte et al. 2014, Kessl J J et al. 2003) crystal structure analysis of atovaquone bound cytochrome be1complex of yeast and discussed (Zhang Z et al. 1998 and Kessl J J et al. 2003) elaborately different binding features of the drug molecule but it is limited to trans-atovaquone only. Unlike our previous model (Nayek S K, Basumallick S et al. 2013) , here we have excluded H2O assisted H bonding interaction between Glu272 and atovaquone as this interaction is absent in the experimentally determined crystal structure (Hunte et al. 2014) of atovaquone