title: Identification of novel antimalarial chemotypes via chemoinformatic compound selection methods for a high-throughput screening program against the novel malarial target, PfNDH2: increasing hit rate via virtual screening methods.
abstract: Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria.
authors.affiliation: Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Lawrenson
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Fisher
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Warman
authors.forename: Alison E
authors.initials: AE
authors.lastname: Shone
authors.forename: Alasdair
authors.initials: A
authors.lastname: Hill
authors.forename: Alison
authors.initials: A
authors.lastname: Mbekeani
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Pidathala
authors.forename: Richard K
authors.initials: RK
authors.lastname: Amewu
authors.forename: Suet
authors.initials: S
authors.lastname: Leung
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbons
authors.forename: David W
authors.initials: DW
authors.lastname: Hong
authors.forename: Paul
authors.initials: P
authors.lastname: Stocks
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Nixon
authors.forename: James
authors.initials: J
authors.lastname: Chadwick
authors.forename: Joanne
authors.initials: J
authors.lastname: Shearer
authors.forename: Ian
authors.initials: I
authors.lastname: Gowers
authors.forename: David
authors.initials: D
authors.lastname: Cronk
authors.forename: Serge P
authors.initials: SP
authors.lastname: Parel
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D001499:Bayes Theorem; D016208:Databases, Factual; D057166:High-Throughput Screening Assays; D048088:Informatics; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D025341:Principal Component Analysis; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases