Development of Inhibitors of Plasmodium falciparum Apical Membrane Antigen 1 Based on Fragment Screening

San Sui Lim,Cael O Debono,Christopher A Macraild,Indu R Chandrashekaran,Olan Dolezal,Robin F Anders,Jamie S Simpson,Martin J Scanlon,Shane M Devine,Peter J Scammells,Raymond S Norton

AUSTRALIAN JOURNAL OF CHEMISTRY（2014）

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摘要

Apical membrane antigen 1 (AMA1) is an essential component of the moving junction complex used by Plasmodium falciparum to invade human red blood cells. AMA1 has a conserved hydrophobic cleft that is the site of key interactions with the rhoptry neck protein complex. Our goal is to develop small molecule inhibitors of AMA1 with broad strain specificity, which we are pursuing using a fragment-based approach. In our screening campaign, we identified fragments that bind to the hydrophobic cleft with a hit rate of 5%. The high hit rate observed strongly suggests that a druggable pocket is present within the cleft.

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关键词

amino acids,combinatorial chemistry,inorganic chemistry,pharmaceutical chemistry,educational,photochemistry,quantum chemistry,ionic liquids,polymer chemistry,kinetics,nanotechnology,organic chemistry,self assembly,mass spectrometry,sensors,biological chemistry,macromolecules,supramolecular chemistry,electrochemistry,structure,biocatalysis,catalysis,interfaces,biosensors,ab initio calculations,crystallography,crystal structures,green chemistry,spectroscopy,density functional theory,physical chemistry,peptide,computational chemistry,reaction mechanisms,combinatorial,proteins,medicinal chemistry,surface chemistry,analytical chemistry,colloids,enzymes

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