Eugene Megnassan, Melalie Keita, Cecile Bieri, Akori Esmel, Vladimir Frecer and Stanislav Miertus Pages 970 - 984 ( 15 )
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.
Plasmodium Falciparum, Lactate Dehydrogenase, Quantitative Structure-activity Relationships (QSAR), Molecular Modeling, Structure-based Drug Design, ADME-related Properties Prediction, Binding Specificity
International Centre for Applied Research and Sustainable Technology (ICARST), Jamnickeho 19, Bratislava SK-84104, Slovakia.