Computational characterisation of Toxoplasma gondii FabG (3-oxoacyl-[acyl-carrier-protein] reductase): a combined virtual screening and all-atom molecular dynamics simulation study

Abstract

Toxoplasma gondii is an opportunistic obligate parasite, ubiquitous around the globe with seropositivity rates that range from 10% to 90% and infection by the parasite of pregnant women causes pre-natal death of the foetus in most cases and severe neurodegenerative syndromes in some. No vaccine is currently available, and since drug-resistance is common among T. gondii strains, discovering lead compounds for drug design using diverse tactics is necessary. In this study, the sole constituent isoform of an enzymatic 3-oxoacyl-[acyl-carrier-protein] reduction step in an apicoplast-located fatty acid biosynthesis pathway was chosen as a possible drug target. FASII is prokaryotic therefore, targeting it would pose fewer side-effects to human hosts. After a homology 3D modelling of TgFabG, a high-throughput virtual screening of 9867 compounds, the elimination of ligands was carried out by a flexible ligand molecular docking and 200 ns molecular dynamics simulations, with additional DCCM and PC plot analyses. Molecular Dynamics and related post-MD analyses of the top 3 TgFabG binders selected for optimal free binding energies, showed that L2 maintained strong H-bonds with TgFabG and facilitated structural reorientation expected of FabGs, namely an expansion of the Rossmann Fold and a flexible lid capping. The most flexible TgFabG sites were the α7 helix (the flexible lid region) and the β4-α4 and β5-α6 loops. For TgFabG-L2, the movements of these regions toward the active site enabled greater ligand stability. Thus, L2 ("Skimmine"; PubChem ID: 320361), was ultimately selected as the optimal candidate for the discovery of lead compounds for rational drug design.

Communicated by Ramaswamy H. Sarma

Keywords:

• Toxoplasma gondii
• 3-oxoacyl-[acyl-carrier-protein] reductase
• FabG
• structure-based drug design
• fatty acid synthesis
• FASII

Acknowledgement

All molecular dynamics simulations reported were performed utilising TÜBİTAK (The Scientific and Technological Research Council of Turkey) ULAKBİM (Turkish Academic Network and Information Centre), High Performance and Grid Computing Centre (TRUBA resources). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Marmara University BAPKO/Scientific Research Projects Unit (Project Grant No: FEN-C-YLP-120418-0171).