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Fragment‐Based Phenotypic Lead Discovery: Cell‐Based Assay to Target Leishmaniasis
Author(s) -
Ayotte Yann,
Bilodeau François,
Descoteaux Albert,
LaPlante Steven R.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800161
Subject(s) - phenotypic screening , amastigote , drug discovery , axenic , leishmania , computational biology , small molecule , biology , chemical library , phenotype , lead compound , fragment (logic) , leishmaniasis , in vitro , bioinformatics , biochemistry , genetics , computer science , gene , parasite hosting , programming language , world wide web , bacteria
A rapid and practical approach for the discovery of new chemical matter for targeting pathogens and diseases is described. Fragment‐based phenotypic lead discovery (FPLD) combines aspects of traditional fragment‐based lead discovery (FBLD), which involves the screening of small‐molecule fragment libraries to target specific proteins, with phenotypic lead discovery (PLD), which typically involves the screening of drug‐like compounds in cell‐based assays. To enable FPLD, a diverse library of fragments was first designed, assembled, and curated. This library of soluble, low‐molecular‐weight compounds was then pooled to expedite screening. Axenic cultures of Leishmania promastigotes were screened, and single hits were then tested for leishmanicidal activity against intracellular amastigote forms in infected murine bone‐marrow‐derived macrophages without evidence of toxicity toward mammalian cells. These studies demonstrate that FPLD can be a rapid and effective means to discover hits that can serve as leads for further medicinal chemistry purposes or as tool compounds for identifying known or novel targets.