The growing resistance to the current antimalarial drugs in the absence of a vaccine can be effectively tackled by identifying new metabolic pathways that are essential to the survival of the malaria parasite and developing new drugs against them. Triterpenes and steroids are the most abundant group of natural products with a great variety of biological activities. However, lanosterol is not known to possess any significant biological activity. In this study the binding and interactions of a dinitrophenyl hydrazine (DNP) derivative of lanosterol, LAN (a derivative that incorporates a substantially polar moiety into the steroid) with P. falciparum transketolase was studied by molecular docking and MD simulation with the view to exploit the DNP derivative as a lead in antimalarial chemotherapy development considering that the P. falciparum transketolase (PfTk) is a novel target in antimalarial chemotherapy. The enzyme catalyses the production of ribose sugars needed for nucleic acid synthesis; it lacks a three-dimensional (3D) structure necessary for docking because it is difficult to obtain a crystalline form. A homology model of PfTk was constructed using Saccharomyces cerevisiae transketolase (protein data bank ID of 1TRK) as the template. The compound was observed to have Free Energy of Binding higher than that of the cofactor of the protein (Thiamine Pyrophosphate, TPP) and a synthetic analog (SUBTPP) used as reference compounds after MD Simulation. The compound was synthesized in a two-step, one-pot reaction, utilizing a non-acidic and mild oxidant to oxidize the lanosterol in order to avoid the rearrangement that accompanies the oxidation of sterols using acidic oxidants. The LAN was characterized using IR spectroscopy and NMR experiments and tested in-vivo for its antimalarial chemo suppression using a murine model with Chloroquine as a standard. The LAN at a concentration of 25 mg/kg was found to have a comparable activity with Chloroquine at 10 mg/kg and no mortality was observed among the test animals 24 days post drug administration showing that the compound indeed has potential as an antimalarial agent and a likely inhibitor of PfTk considering that there is a strong agreement between the in-silico results and biological study.
Supplementary information: The online version contains supplementary material available at 10.1007/s40203-021-00097-8.
Keywords: Chemo suppression; Homology modelling; Molecular dynamics; Synthesis; Transketolase.
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.