title: Design of novel dihydroxynaphthoic acid inhibitors of Plasmodium falciparum lactate dehydrogenase.
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.
authors: University of Abobo Adjamé, Laboratoire de Physique Fondamentale et Appliquée, 02 BP 801, Abidjan 02, Cote D'Ivoire.
authors: Eugene
authors: E
authors: Megnassan
authors: Melalie
authors: M
authors: Keita
authors: Cecile
authors: C
authors: Bieri
authors: Akori
authors: A
authors: Esmel
authors: Vladimir
authors: V
authors: Frecer
authors: Stanislav
authors: S
authors: Miertus
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry; D001393:Azoles / Q000737:chemistry; D001665:Binding Sites; D003369:Cottonseed Oil / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D013045:Species Specificity
chemical_list: D000962:Antimalarials; D001393:Azoles; D003369:Cottonseed Oil; D007527:Isoenzymes; D015800:Protozoan Proteins; D012717:Sesquiterpenes; D007770:L-Lactate Dehydrogenase