Identification of Candidate Inhibitory Ligands from Allium cepa and Molecular Docking Against Trypanosma brucei Phosphoglycerate Kinase; The In-Silico Structure-Activity Relationship

S. Cosmas, O.A Durojaye^*, R. O Asomadu, I. N Amorha, O. I Diyoke, G. A Osegbo
Department of Biochemistry, University of Nigeria, Nsukka

A B S T R A C T
Trypanosoma brucei is a unicellular parasite causing African sleeping sickness in cattle and humans. Infection occurs when a vector tsetse fly bites a mammalian host. The fly injects the metacyclic trypomastigotes into the skin tissue. The trypomastigotes enter the lymphatic system and into the bloodstream. The initial trypomastigotes are short and stumpy. Once inside the bloodstream, they grow into long and slender forms. Then, they multiply by binary fission. Onion (Allium cepa) contains a high level of dietary flavonoids with evidences indicating they exhibit antiparasitic effects. A molecular docking study was carried out on five structurally similar Allium cepa flavonoids against Trypanosoma brucei phosphoglycerate kinase using the Autodock Vina software. Extensive structure activity relationship study was also carried out with these molecules.  The physicochemical analysis, lipophilicity, solubility, pharmacokinetics and Lipinski druglikeness of Apigenin, Kaempferol, Luteolin, Myricetin and Quercetin were evaluated. These molecules were designed using the ChemAxon software. The scoring function (empirical binding free energy) was used to estimate the inhibitory activity of the protein-ligand complex. The binding energy of apigenin, kaempferol, luteolin, myricetin and quercetin were -7.7, -7.6, -7.7, -7.5 and -7.6Kcal/mol respectively while the number of hydrogen bonds formed with the target enzyme were 8, 6, 10, 7, 7 respectively. The low values (negative) of free binding energies displayed by the bioactive components of Allium cepa means that they show a high level of antiparasitic activity, while the higher number of hydrogen bonds formed by the luteolin component indicates a higher binding affinity with the target enzyme. While the myricetin component showed a poor GI absorption rate, all the flavnoids do not cross the blood brain barrier (BBB) showing that they cannot cause problem to the brain. These results clearly indicated that the luteolin substituents may be a better antiparasitic agent, having exhibited the best binding affinity with the Trypanosma brucei Phosphoglycerate kinase. Laboratory synthesis and pre-clinical studies of the luteolin component with Trypanosoma brucei phosphoglycerate kinase is recommended in order to confirm its potentials as a better antiparasitic agent than the other Allium cepa flavonoids.
Keywords: Infection, Flavonoids, Molecular docking, Pharmacokinetics, Lipophilicity