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Homology modeling and SAR analysis of Schistosoma japonicum cathepsin D (SjCD) with statin inhibitors identify a unique active site steric barrier with potential for the design of specific inhibitors

  • Conor R. Caffrey , Lenka Placha , Cyril Barinka , Martin Hradilek , Jiří Dostál , Mohammed Sajid , James H. McKerrow , Pavel Majer , Jan Konvalinka and Jiří Vondrášek
Published/Copyright: July 5, 2005
Biological Chemistry
From the journal Volume 386 Issue 4

Abstract

Proteases that digest the blood-meal of the parasitic fluke Schistosoma are potential targets for therapy of schistosomiasis, a disease of chronic morbidity in humans. We generated a three-dimensional model of the cathepsin D target protease of Schistosoma japonicum (SjCD) utilizing the crystal structure of human cathepsin D (huCD) in complex with pepstatin as template. A homology model was also generated for the related secreted aspartic protease 2 (SAP2) of the pathogenic yeast, Candida albicans. An initial panel of seven statin inhibitors, originally designed for huCD [Majer et al., Protein Sci. 6 (1997), pp. 1458–1466], was tested against the two pathogen proteases. One inhibitor showed poor reactivity with SjCD. Examination of the SjCD active-site cleft revealed that the poor inhibition was due to a unique steric barrier situated between the S2 and S4 subsites. An in silico screen of 20 potential statin scaffolds with the SjCD model and incorporating the steric barrier constraint was performed. Four inhibitors (SJ1–SJ4) were eventually synthesized and tested with SjCD, bovine CD and SAP2. Of these, SJ2 and SJ3 proved moderately more specific for SjCD over bovine CD, with IC50 values of 15 and 60 nM, respectively. The unique steric barrier identified here provides a structural focus for further development of more specific SjCD inhibitors.

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Published Online: 2005-07-05
Published in Print: 2005-04-01

© by Walter de Gruyter Berlin New York

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