title: Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits.
abstract: Methods to discover biologically active small molecules include target-based and phenotypic screening approaches. One of the main difficulties in drug discovery is elucidating and exploiting the relationship between drug activity at the protein target and disease modification, a phenotypic endpoint. Fragment-based drug discovery is a target-based approach that typically involves the screening of a relatively small number of fragment-like (molecular weight <300) molecules that efficiently cover chemical space. Here, we report a fragment screening on TbrPDEB1, an essential cyclic nucleotide phosphodiesterase (PDE) from Trypanosoma brucei, and human PDE4D, an off-target, in a workflow in which fragment hits and a series of close analogs are subsequently screened for antiparasitic activity in a phenotypic panel. The phenotypic panel contained T. brucei, Trypanosoma cruzi, Leishmania infantum, and Plasmodium falciparum, the causative agents of human African trypanosomiasis (sleeping sickness), Chagas disease, leishmaniasis, and malaria, respectively, as well as MRC-5 human lung cells. This hybrid screening workflow has resulted in the discovery of various benzhydryl ethers with antiprotozoal activity and low toxicity, representing interesting starting points for further antiparasitic optimization.
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Antoni R
authors.initials: AR
authors.lastname: Blaazer
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands TI Pharma, Leiden, The Netherlands.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Orrling
authors.affiliation: IOTA Pharmaceuticals, Cambridge, UK.
authors.forename: Anitha
authors.initials: A
authors.lastname: Shanmugham
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands University of Dundee, Dundee, UK.
authors.forename: Chimed
authors.initials: C
authors.lastname: Jansen
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ewald
authors.initials: E
authors.lastname: Edink
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Sterk
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Siderius
authors.affiliation: IOTA Pharmaceuticals, Cambridge, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: England
authors.affiliation: IOTA Pharmaceuticals, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bailey
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands r.leurs@vu.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D058069:Neglected Diseases / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests / Q000379:methods*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; C581006:PDEB1 protein, Trypanosoma brucei
keywords: antiparasitic activity; cell-based screening; fragment-based drug discovery (FBDD); neglected tropical diseases (NTDs); phenotypic drug discovery (PDD); phenotypic screening; phosphodiesterase (PDE) inhibitors