Abstract
Context: Malaria remains one of the prevalent infectious diseases worldwide. Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase (PfDXR) plays a role in isoprenoid biosynthesis in the malaria parasite, making this parasite enzyme an attractive target for antimalarial drug design. Fosmidomycin is a promising DXR inhibitor, which showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. However, due to its poor oral bioavailability and non-drug-like properties, the focus of medicinal chemists is to develop inhibitors with improved pharmacological properties. Objective: This study described the computational design of new and potent inhibitors for deoxyxylulose 5-phosphate reductoisomerase and the prediction of their pharmacokinetic and pharmacodynamic properties. Material and methods: A complex-based pharmacophore model was generated from the complex X-ray crystallographic structure of PfDXR using MOE (Molecular Operating Environment). Furthermore, MOE-Dock was used as docking software to predict the binding modes of hits and target enzyme. Results: Finally, 14 compounds were selected as new and potent inhibitors of PfDXR on the basis of pharmacophore mapping, docking score, binding energy and binding interactions with the active site residues of the target protein. The predicted pharmacokinetic properties showed improved permeability by efficiently crossing blood–brain barrier. While, in silico promiscuity binding data revealed that these hits also have the ability to bind with other P. falciparum drug targets. Discussion and conclusion: In conclusion, innovative scaffolds with novel modes of action, improved efficacy and acceptable physiochemical/pharmacokinetic properties were computationally identified.
Highlights
In 2014, the World Health Organization (WHO) reported an estimated 198 million cases of malaria worldwide, and 584,000 subsequent deaths from the disease, mostly among children below five years of age (Zhang et al 2015; Bertin et al 2016)
Pharmacophore modelling has been widely used in drug discovery and is considered an important technique for its use in virtual screening
The current study describes the use of a complex-based pharmacophore model, determines interaction points from structural data of receptor-ligand complex to lead the improvement of binding affinity and increasing selectivity
Summary
In 2014, the World Health Organization (WHO) reported an estimated 198 million cases of malaria worldwide, and 584,000 subsequent deaths from the disease, mostly among children below five years of age (Zhang et al 2015; Bertin et al 2016). Anopheles mosquitoes cause malaria in human and cause infection by intracellular parasites, i.e., Plasmodium (Winzeler 2008). There are four species of the Plasmodium, and Plasmodium falciparum is the most dangerous one that causes infection in human beings. P. falciparum is highly resistant to various antimalarial drugs, for example amodiaquine, sulphadoxinepyrimethamine and chloroquine. P. falciparum is a multidrug resistant species and cause malaria, so for its treatment new antimalarial drugs with novel modes of action are urgently needed. Emergence of resistance in P. falciparum strains has hampered the treatment of malaria and has been one of the major challenges for medicinal/drug discovery chemists. There are several malarial enzymes and pathways, such as nucleic acid metabolism, oxidative stress that can serve as a potential validated drug targets for antimalarial drug design. There are several malarial enzymes and pathways, such as nucleic acid metabolism, oxidative stress that can serve as a potential validated drug targets for antimalarial drug design. 2-Methyl-D-erythritol-4-
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