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RESEARCH FRONT
Contents Vol 66(12)

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

San Sui Lim A , Cael O. Debono A , Christopher A. MacRaild A , Indu R. Chandrashekaran A , Olan Dolezal B , Robin F. Anders C , Jamie S. Simpson A , Martin J. Scanlon A D , Shane M. Devine A , Peter J. Scammells A and Raymond S. Norton A E
+ Author Affiliations
- Author Affiliations

A Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic. 3052, Australia.

B CSIRO Materials Science and Engineering, Parkville, Vic. 3052, Australia.

C Department of Biochemistry, La Trobe University, Bundoora, Vic. 3086, Australia.

D Centre of Excellence for Coherent X-Ray Science, Monash University, Parkville, Vic. 3052, Australia.

E Corresponding author. Email: ray.norton@monash.edu

Australian Journal of Chemistry 66(12) 1530-1536 https://doi.org/10.1071/CH13266
Submitted: 22 May 2013  Accepted: 29 July 2013   Published: 26 August 2013

Abstract

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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