The process of drug discovery is considered as one of the longest and costliest efforts. The classical approach to drug discovery process is the identification of drug target, then designing the lead compound, and finally the validation of the compounds through clinical trials. It was considered that on an average one new drug takes approximately 12-13 years to reach to a patient from a research laboratory. Millions have been spent to find some new drug candidates for the particular disease, but the success rate is very low. The reason could be the limited knowledge of complex biological systems. Therefore, it was perceived that until in-depth knowledge of the complex biological process that leads to the diseased state is considered, the discovery of new drug will be a time-consuming and challenging process. Well known compounds have been discovered by serendipity. The best-known drug is Artemisinin, the present frontline drug for treatment of Malaria. Many combinatorial substitutions have been synthesized and inhibition was tested for more than 100 compounds, analogs of Artemisinin, but the single target has yet not been identified. So the widespread promiscuity about its mechanism of action is a challenge to designing better compound from this. Recent studies are shown the resistance is also growing, which can only be resolved if the actual binding target is known. In search for the plausible mechanism of action, a calcium pump called PfATP6 has been investigated to understand the role of iron and Artemisinin on PfATP6 and compared with human homolog protein. During the binding, a closure between different domain like phosphorylation, nucleotide binding and actuator domains happen, this stops Ca⁺⁺ to enter and the loss of function of PfATP6. Comparing the human Ca⁺⁺/ATPase (SERCA), it was found that such activity is not possible, which reflects in low IC50 of binding of Artemisinin to human. An attempt has been made to design appropriate Pharmacophore model using available Artemisinin analogs and the binding to the open and close conformation of calcium pump PfATP6. Two different methods have been used to develop diverse pharmacophore features that may be utilized for either screening databases for non-sesquiterpene lactone scaffold based inhibitor identification or probing the role of flexibility by docking the pharmacophore features in the binding site of the target protein. The present study will provide validation of such mechanism and help in the design of novel antimalarial. Many tools like density functional theory calculations, pharmacophore generation, docking and molecular dynamics simulations are used efficiently to find that Artemisinin gets activated in the presence of iron and then only can inhibit PfATP6.