Chloroquine binds in the cofactor binding site of Plasmodium falciparum lactate dehydrogenase

Although the molecular mechanism by which chloroquine exerts its effects on the malarial parasite Plasmodium falciparum remains unclear, the drug has previously been found to interact specifically with the glycolytic enzyme l actate dehydrogenase from the parasite. In this study we have determined th e crystal structure of the complex between chloroquine and P. falciparum la ctate dehydrogenase. The bound chloroquine is clearly seen within the NADH binding pocket of the enzyme, occupying a position similar to that of the a denyl ring of the cofactor. Chloroquine hence competes with NADH for bindin g to the enzyme, acting as a competitive inhibitor for this critical glycol ytic enzyme. Specific interactions between the drug and amino acids unique to the malarial form of the enzyme suggest this binding is selective. Inhib ition studies confirm that chloroquine acts as a weak inhibitor of lactate dehydrogenase, with mild selectivity for the parasite enzyme. As chloroquin e has been shown to accumulate to millimolar concentrations within the food vacuole in the gut of the parasite, even low levels of inhibition may cont ribute to the biological efficacy of the drug, The structure of this enzyme -inhibitor complex provides a template from which the quinoline moiety migh t be modified to develop more efficient inhibitors of the enzyme.