title: Fighting malaria: structure-guided discovery of nonpeptidomimetic plasmepsin inhibitors.
abstract: Plasmepsins (Plms) are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress has been achieved in the development of inhibitors of plasmepsin using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by SBDD or SBVS with a particular focus on obtaining selectivity versus the human Asp proteases cathepsins and renin and activity in cell-based assays. By use of SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I-IV and selectivity versus cathepsins are not always taken into account. A combination of SBVS, SBDD, and molecular dynamics simulations opens up opportunities for future design cycles.
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, NL-9747 AG Groningen, The Netherlands.
authors.forename: Anja P
authors.initials: AP
authors.lastname: Huizing
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, NL-9747 AG Groningen, The Netherlands.
authors.forename: Milon
authors.initials: M
authors.lastname: Mondal
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, NL-9747 AG Groningen, The Netherlands.
authors.forename: Anna K H
authors.initials: AK
authors.lastname: Hirsch
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin