Abstract
A recent rational approach to anti-malarial drug design is characterized as “covalent biotherapy” involves linking of two molecules with individual intrinsic activity into a single agent, thus packaging dual activity into a single hybrid molecule. In view of this background and reported anti malaria synergism between artemisinin and quinine; we describe the computer-assisted docking to predict molecular interaction and binding affinity of Artemisinin-Quinine hybrid and its derivatives with the intraparasitic haeme group of human haemoglobin. Starting from a crystallographic structure of Fe-protoporphyrin-IX, binding modes, orientation of peroxide bridge (Fe-O distance), docking score and interaction energy are predicted using the docking molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Seven new ligands were identified with a favourable glide score (XP score) and binding free energy (ΔG) with reference to the experimental structure from a data set of thirty four hybrid derivatives. The result shows the conformational property of the drug-receptor interaction and may lead to rational design and synthesis of improved potent artemisinin based hybrid antimalarial that target haemozoin formation.
Highlights
Malaria is a non-contagious disease of chronic evolution that manifests in acute episodes [1]
It has been demonstrated that Plasmodium falciparum, the causative agent of almost all fatal cases of malaria, detoxifies host haemoglobin-derived ferriprotoporphyrin IX (Fe (III) PPIX) in an acidic digestive vacuole (DV) mainly by converting it to haemozoin [2]
Fe (III) PPIX produced by autoxidation of haeme (Fe (II) PPIX) released from haemoglobin is known to be capable of causing lipid peroxidation [2] and to destabilize membranes through a colloid osmotic mechanism [2]
Summary
Malaria is a non-contagious disease of chronic evolution that manifests in acute episodes [1]. It was suggested that coupling of the slow-acting, relatively polar quinine derivative might increase the half-life of the artemisinin moiety Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs [10]. Sub lib-II: Artemisinin-Quinine Hybrid - This library consists of five ligands which are designed by attachment of Quinine moiety to the Artemisinin molecule at O-14. Sub lib-VI: Seco Artemisinin-Quinine Hybrid-This library is having three ligands (16-18) with logP in the range from 5.22 to 5.79.The Quinine molecule is attached to the seco artemisinin entity at C9 carbon atom. Sub lib-VII: Miscellaneous Artemisinin-Quinine Hybrid- This library consists of four ligand in which various substitutions in different carbon atom of Artemisinin molecule are attached to the Quinine entity. Corrections for entropic changes were not applied in this type of free energy calculation
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