Computational screening of molecular targets in Plasmodium for novel non resistant anti-malarial drugs

Histone acetyltransferase (HAT) is an enzyme required for chromatin remodeling and transcriptional activation. Sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) is an ATP coupled Ca2+ ion pump involved in metabolic arrest. Both these enzymes are present in Plasmodia and have been selected as molecular targets for in silico studies of some new non-resistant antimalarial drugs like artemisinin, curcumin and diarylheptanoids along with some other inhibitors reported in literature. Ten top inhibitors have also been generated based on common pharmacophore from ZINC database. The HAT enzyme was modeled with the help of the Modeller software and the SERCA enzyme pdb file was obtained from the protein data bank. Ligbuilder was used for structure based drug designing, which generated a common pharmacophore of the ligands. Molegro was used to perform virtual screening of the hits from the pharmacophore based Zinc database search and known inhibitors of the enzymes from the literature survey. Curcumin shows good and optimal binding to both HAT and SERCA enzymes; therefore it might be a good inhibitor of these key enzymes in Plasmodium. Curcumin is reported to act synergistically with artemisinin which forms covalent adducts with the transmembrane proteins (SERCA enzyme) and inactivates them, thus inhibiting the activity of Plasmodium parasite. This combination has already been reported to be effective in malaria treatment. Some other diarylheptanoids besides curcumin showed better binding to both the enzymes. Therefore, a combination of artemisinin and diarylheptanoids can prove to be better combination for antimalarial therapy. Different formulations involving curcumin, artimisinin and diarylheptanoids may result in a more potent antimalarial drug.