A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II K i values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2′ pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar Ki values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a Ki value of 35 nM. © 2005 American Chemical Society.
CITATION STYLE
Ersmark, K., Nervall, M., Hamelink, E., Janka, L. K., Clemente, J. C., Dunn, B. M., … Hallberg, A. (2005). Synthesis of malarial plasmepsin inhibitors and prediction of binding modes by molecular dynamics simulations. Journal of Medicinal Chemistry, 48(19), 6090–6106. https://doi.org/10.1021/jm050463l
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