Design of Novel Dihydroxynaphthoic Acid Inhibitors of Plasmodium Falciparum Lactate Dehydrogenase

Author(s): Eugene Megnassan, Melalie Keita, Cecile Bieri, Akori Esmel, Vladimir Frecer, Stanislav Miertus.

Journal Name: Medicinal Chemistry

Volume 8 , Issue 5 , 2012

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Abstract:

We have studied inhibition of Plasmodium falciparum lactate dehydrogenase (pfLDH) by dihydroxynaphthoic acid (DHNA) analogues derivatives of hemigossypol-sesquiterpene found in cottonseed known to exhibit antimalarial activity. Molecular models of pfLDH-DHNA complexes were prepared from high-resolution crystal structures containing DHNA and azole inhibitors and binding affinities of the inhibitors were computed by molecular mechanics – polarizable continuum model of solvation (MM-PCM) approach. The 3D structures of the pfLDH-DHNA complexes were validated by a QSAR model, which confirmed consistency between the computed binding affinities and experimental inhibition constants for a training set and validation set of twelve DHNA inhibitors obtained from literature. Novel more potent DHNA analogs were identified by structure-based molecular design and predicted to inhibit pfLDH in the low nanomolar concentration range. In addition, the designed DHNA analogs displayed favorable predicted ADME-related profiles and an elevated selectivity for the pfLDH over the human isoform.

Keywords: Plasmodium Falciparum, Lactate Dehydrogenase, Quantitative Structure-activity Relationships (QSAR), Molecular Modeling, Structure-based Drug Design, ADME-related Properties Prediction, Binding Specificity

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Article Details

VOLUME: 8
ISSUE: 5
Year: 2012
Page: [970 - 984]
Pages: 15
DOI: 10.2174/157340612802084324
Price: $58

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