Unveiling a New Era in Malaria Therapeutics: A Tailored Molecular Approach Towards the Design of Plasmepsin IX Inhibitors.

The invasive tactics employed by the malarial parasite renders malaria a global health threat, further impeding the effective treatment of the mosquito borne-parasitic disease. Although there have been countless efforts directed towards the development of effective therapeutics, factors such as emerging strains of drug resistance, enhanced toxicity and poor pharmacokinetic properties of current therapeutics has hampered the drug discovery process resulting in the spread of this parasitic disease. A promising target of the most lethal strain of the Plasmodium species that plays a predicted role in erythrocyte invasion of the virulent malarial parasite is aspartic protease IX commonly referred to Plasmepsin IX. The integration of computer aided-drug design platforms has revolutionized the 21st century and has opened avenues to render a final "knock out" in the elimination and eradication of this parasitic disease Hitherto, this is the first attempt directed towards the design of therapeutics tailored explicitly to Plasmepsin IX. A potent peptidomimetic inhibitor referred to as 49c which is a known inhibitor of Plasmepsin II, has recently exhibited potent inhibitory activity against Plasmepsin IX. In-silico structural and physicochemical inspection of 49c displayed poor pharmacokinetic properties thus paving the way for the development of tailored inhibitors with desirable therapeutic properties against Plasmepsin IX. In this study we implement the pharmacophore model approach in combination with per-residue energy decomposition analysis to serve as a powerful cornerstone, that may assist medicinal experts in the composition of multifunctional therapeutics that may predispose factors such as cross-resistance and toxicity, with enhanced pharmacokinetic properties.