title: Structural analysis of chorismate synthase from Plasmodium falciparum: a novel target for antimalaria drug discovery.
abstract: The shikimate pathway in Plasmodium falciparum provides several targets for designing novel antiparasitic agents for the treatment of malaria. Chorismate synthase (CS) is a key enzyme in the shikimate pathway which catalyzes the seventh and final step of the pathway. P. falciparum chorismate synthase (PfCS) is unique in terms of enzymatic behavior, cellular localization and in having two additional amino acid inserts compared to any other CS. The structure of PfCS along with cofactor FMN was predicted by homology modeling using crystal structure of Helicobacter pylori chorismate synthase (HpCS). The quality of the model was validated using structure analysis servers and molecular dynamics. Dimeric form of PfCS was generated and the FMN binding mechanism involving movement of loop near active site has been proposed. Active site pocket has been identified and substrate 5-enolpyruvylshikimate 3-phosphate (EPSP) along with screened potent inhibitors has been docked. The study resulted in identification of putative inhibitors of PfCS with binding efficiency in nanomolar range. The selected putative inhibitors could lead to the development of anti-malarial drugs.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India. satyadbt@iitr.ernet.in
authors.forename: Satya
authors.initials: S
authors.lastname: Tapas
authors.forename: Abhinav
authors.initials: A
authors.lastname: Kumar
authors.forename: Sonali
authors.initials: S
authors.lastname: Dhindwal
authors.lastname: Preeti
authors.forename: Pravindra
authors.initials: P
authors.lastname: Kumar
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000494:pharmacology*; D020134:Catalytic Domain; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005486:Flavin Mononucleotide / Q000737:chemistry / Q000378:metabolism; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D019761:Phosphorus-Oxygen Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D012765:Shikimic Acid / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D012765:Shikimic Acid; D005486:Flavin Mononucleotide; C019895:chorismate synthase; D019761:Phosphorus-Oxygen Lyases