title: New paradigm of an old target: an update on structural biology and current progress in drug design towards plasmepsin II.
abstract: Malaria is one of the major parasitic disease whose rapid spreading and mortality rate affects all parts of the world especially several parts of Asia as well as Africa. The emergence of multi-drug resistant strains hamper the progress of current antimalarial therapy and displayed an urgent need for new antimalarials by targeting novel drug targets. Until now, several promising targets were explored in order to develop a promising Achilles hill to counter malaria. Plasmepsin, an aspartic protease, which is involved in the hemoglobin breakdown into smaller peptides emerged as a crucial target to develop new chemical entities to counter malaria. Due to early crystallographic evidence, plasmepsin II (Plm II) emerged as well explored target to develop novel antimalarials as well as a starting point to develop inhibitors targeting some other subtypes of plasmepsins i.e. Plm I, II, IV and V. With the advancements in drug discovery, several computational and synthetic approaches were employed in order to develop novel inhibitors targeting Plm II. Strategies such as fragment based drug design, molecular dynamics simulation, double drug approach etc. were employed in order to develop new chemical entities targeting Plm II. But majority of Plm II inhibitors suffered from poor selectivity over cathepsin D as well as other subtypes of plasmepsins. This review highlights an updated account of drug discovery efforts targeting plasmepsin II from a medicinal chemistry perspective.
authors.affiliation: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra 835215, India.
authors.forename: Nirnoy
authors.initials: N
authors.lastname: Dan
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa. Electronic address: bhakatsoumendranath@gmail.com.
authors.forename: Soumendranath
authors.initials: S
authors.lastname: Bhakat
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D058990:Molecular Targeted Therapy / Q000379:methods*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II
keywords: Aspartic protease; Drug discovery; Malaria; Peptidomimetics; Plasmepsin II; Protease inhibitor