title: Drug target prioritization in Plasmodium falciparum through metabolic network analysis, and inhibitor designing using virtual screening and docking approach.
abstract: The genome sequence of Plasmodium falciparum reveals that many metabolic pathways are unique as compared to its human host. Metabolic Network Analysis was carried out to find the essential enzymes critical for the survival of the pathogen. In the present study, choke point and load point analysis was used to locate putative targets. The identified targets were further checked to confirm that no alternate pathway or human homolog exists. Among the top 15 enzymes obtained from this analysis, we have selected P. falciparum orotidine-5'-monophosphate decarboxylase (PfODCase) enzyme as it is sequentially and structurally different from that of humans, for searching novel inhibitors. A five-point 3D pharmacophore was generated for the crystal structure of PfODCase complexes with uridine-5'-monophosphate (U5P). The binding site environment shows three H-bond acceptors, one H-bond donor and one negative ionizable feature. This pharmacophore model was used as a 3D query to perform virtual screening experiments against 2,664,779 standard lead compounds obtained from the freely available ZINC database. Top 10 hits obtained from virtual screening were selected for molecular docking experiments against PfODCase in order to verify their results and to have a better insight into their binding modes. Here, docking of U5P with PfODCase is used as a control. We have identified six compounds, among them, few are U5P analogs and others are novel ones with diverse scaffolds. The key residues: Lys42, Asp20, Lys72, Ser127, Ala184, Gln185 and Arg203 at the main binding pocket of PfODCase are responsible for better stability of diverse ligands. These compounds according to their free energy of binding could serve as potent leads for designing novel inhibitors against malarial ODCase enzyme.
authors.affiliation: Department of Bioinformatics, MMV, Banaras Hindu University, Varanasi 221005, India. manojiids@gmail.com
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Yadav
authors.forename: Saurabh Kumar
authors.initials: SK
authors.lastname: Pandey
authors.forename: D
authors.initials: D
authors.lastname: Swati
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D053858:Metabolic Networks and Pathways; D062105:Molecular Docking Simulation; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D009964:Orotidine-5'-Phosphate Decarboxylase