title: Plasmepsin inhibitors: design, synthesis, inhibitory studies and crystal structure analysis.
abstract: Plasmepsin group of enzymes are key enzymes in the life cycle of malarial parasites. As inhibition of plasmepsins leads to the parasite's death, these enzymes can be utilized as potential drug targets. Although many drugs are available, it has been observed that Plasmodium falciparum, the species that causes most of the malarial infections and subsequent death, has developed resistance against most of the drugs. Based on the cleavage sites of hemglobin, the substrate for plasmepsins, we have designed two compounds (p-nitrobenzoyl-leucine-beta-alanine and p-nitrobenzoyl-leucine-isonipecotic acid), synthesized them, solved their crystal structures and studied their inhibitory effect using experimental and theoretical (docking) methods. In this paper, we discuss the synthesis, crystal structures and inhibitory nature of these two compounds which have a potential to inhibit plasmepsins.
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
authors.forename: M M
authors.initials: MM
authors.lastname: Kesavulu
authors.forename: A S
authors.initials: AS
authors.lastname: Prakasha Gowda
authors.forename: T N C
authors.initials: TN
authors.lastname: Ramya
authors.forename: N
authors.initials: N
authors.lastname: Surolia
authors.forename: K
authors.initials: K
authors.lastname: Suguna
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007540:Isonipecotic Acids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000187:drug effects; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007540:Isonipecotic Acids; D015091:beta-Alanine; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin