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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