title: Identification of novel malarial cysteine protease inhibitors using structure-based virtual screening of a focused cysteine protease inhibitor library.
abstract: Malaria, in particular that caused by Plasmodium falciparum , is prevalent across the tropics, and its medicinal control is limited by widespread drug resistance. Cysteine proteases of P. falciparum , falcipain-2 (FP-2) and falcipain-3 (FP-3), are major hemoglobinases, validated as potential antimalarial drug targets. Structure-based virtual screening of a focused cysteine protease inhibitor library built with soft rather than hard electrophiles was performed against an X-ray crystal structure of FP-2 using the Glide docking program. An enrichment study was performed to select a suitable scoring function and to retrieve potential candidates against FP-2 from a large chemical database. Biological evaluation of 50 selected compounds identified 21 diverse nonpeptidic inhibitors of FP-2 with a hit rate of 42%. Atomic Fukui indices were used to predict the most electrophilic center and its electrophilicity in the identified hits. Comparison of predicted electrophilicity of electrophiles in identified hits with those in known irreversible inhibitors suggested the soft-nature of electrophiles in the selected target compounds. The present study highlights the importance of focused libraries and enrichment studies in structure-based virtual screening. In addition, few compounds were screened against homologous human cysteine proteases for selectivity analysis. Further evaluation of structure-activity relationships around these nonpeptidic scaffolds could help in the development of selective leads for antimalarial chemotherapy.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi , University, Mississippi 38677, USA.
authors.forename: Falgun
authors.initials: F
authors.lastname: Shah
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Jennifer
authors.initials: J
authors.lastname: Legac
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D004351:Drug Resistance; D006801:Humans; D008288:Malaria; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3