title: Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum.
abstract: BACKGROUND
  In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty.
  
  
  METHODS
  The selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as 'signposts' in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay.
  
  
  RESULTS
  This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC₅₀ < 1 μM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series.
  
  
  CONCLUSIONS
  A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochemical filters, were key to the process. This led to the selection of 15 chemical series from which ten confirmed their activity when newly synthesized sample were tested.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.forename: Sridevi
authors.initials: S
authors.lastname: Bashyam
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.forename: George
authors.initials: G
authors.lastname: Papadatos
authors.forename: Shyni
authors.initials: S
authors.lastname: Puthukkuti
authors.forename: Yuvaraj
authors.initials: Y
authors.lastname: Sambandan
authors.forename: Shivendra
authors.initials: S
authors.lastname: Singh
authors.affiliation: Medicines for Malaria Venture MMV, ICC - Block G, 3rd Floor, route de Pré-Bois 20, PO Box 1826, 1215 Geneva 15, Switzerland. spangenbergt@mmv.org.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spangenberg
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Paul
authors.initials: P
authors.lastname: Willis
mesh_terms: D000465:Algorithms; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries