Molecular Modeling Studies, Synthesis and Biological Evaluation of Novel Plasmodium falciparum Lactate Dehydrogenase (pfLDH) Inhibitors

Premlata      K. Ambre; Raghuvir      R. S. Pissurlenkar; Ashish      S. Jagyasi; Ritesh      A. Fule; Vijay      Khedkar; Chandrashekar      R. Barhate; Livia      Vivas; Abhai      K. Tripathi; David      Sullivan; Richard      Birkinshaw; R.      Leo Brady; Krishna      Iyer; Evans      C. Coutinho

Abstract

In silico methods have been used to identify five different classes of compounds as inhibitors of the essential Plasmodium falciparum enzyme lactate dehydrogenase (LDH). The molecules were assayed for in vitro antimalarial activity in both cell- and enzyme-based inhibition models. 5-Bromo-2-hydroxypyridine-3-carboxylic acid 19 is the most active with IC50 of 3.5 nM for chloroquine sensitive and 5 nM for resistant strains of Plasmodium falciparum, compared to 11 nM and 100 nM for the standard chloroquine. In LDH-enzyme inhibition assays the leading compounds are 5, 10, 18 and 19. Docking studies and the 3D-QSAR technique - CoRIA have been used to identify key binding elements between the molecules and residues in the LDH active site. A bifurcated salt bridge that associates the carboxylate group on the molecules with the guanidino group in the side chain of both Arg109 and Arg171 along with π-stack of the heterocycle with the pyridine ring of the cofactor NAD+, are the prime interactions. In silico ADME/toxicity studies also suggest these molecules have favorable pharmacokinetic and toxicity profiles.

Keywords: Antimalarial agents, CoRIA, docking, lactate dehydrogenase, Plasmodium falciparum, QSAR, Malaria