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Synthesis of malarial plasmepsin inhibitors and prediction of binding modes by molecular dynamics simulations.

Abstract：

: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 Ki 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Ersmark K,Nervall M,Hamelink E,Janka LK,Clemente JC,Dunn BM,Blackman MJ,Samuelsson B,Aqvist J,Hallberg A

doi

10.1021/jm050463l

keywords:

subject

Has Abstract

pub_date

2005-09-22 00:00:00

pages

6090-106

issue

19

eissn

0022-2623

issn

1520-4804

journal_volume

48

pub_type

杂志文章

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