title: Docking studies on the binding of quinoline derivatives and hematin to Plasmodium falciparum lactate dehydrogenase.
abstract: The literature has reported that ferriprotoporphyrin IX (hematin) intoxicates the malarial parasite through competition with NADH for the active site of the enzyme lactate dehydrogenase (LDH). In order to avoid this, the parasite polymerizes hematin to hemozoin. The quinoline derivatives are believed to form complexes with dimeric hematin, avoiding the formation of hemozoin and still inhibiting LDH. In order to investigate this hypothesis we calculated the docking energies of NADH and some quinoline derivatives (in the free forms and in complex with dimeric hematin) in the active site of the Plasmodium falciparum LDH (PfLDH). Ours results showed better docking score values to the complexes when compared to the free compounds, pointing them as more efficient inhibitors of Pf_LDH. Further we performed Molecular Dynamics (MD) simulations studies on the best docking conformation of the complex chloroquine-dimeric hematin with PfLDH. Our in silico results corroborate experimental data suggesting a possible action route for the quinoline derivatives in the inhibition of PfLDH.
authors.affiliation: Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMCBD), Military Institute of Engineering, CEP 22290-270, Rio de Janeiro, RJ, Brazil.
authors.forename: Wilian A
authors.initials: WA
authors.lastname: Cortopassi
authors.forename: Aline A
authors.initials: AA
authors.lastname: Oliveira
authors.forename: Ana P
authors.initials: AP
authors.lastname: Guimarães
authors.forename: Magdalena N
authors.initials: MN
authors.lastname: Rennó
authors.forename: Antoniana U
authors.initials: AU
authors.lastname: Krettli
authors.forename: Tanos C C
authors.initials: TC
authors.lastname: França
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D006427:Hemin / Q000737:chemistry* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000378:metabolism; D011487:Protein Conformation; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D011804:Quinolines; D006427:Hemin; D007770:L-Lactate Dehydrogenase