Ornithine decarboxylase (ODC) catalyzes the decarboxylation of ornithine to putrescine. This is known to be a crucial step for polyamines biosynthesis in Trypanosoma brucei. These polyamines are necessary for microbial cell growth and proliferation. Hence, ODC enzyme is the best target to treat African sleeping sickness disease-causing protozoan parasite, T. brucei. ODC is a 5ʹ-pyridoxal phosphate (PLP) dependent, an obligate homodimer enzyme with two identical active sites at the dimer interface, comprising the beta or alpha barrel domain from one subunit and beta-sheet domain from the other subunit. The catalytic residues are contributed to the active site from both monomers. An X-ray crystallography study on ODC in the wild T. brucei has revealed two structural changes upon ligand binding; an amino acid residue specifically Lys-69 is displaced by putrescine forming a new interaction and a side chain of Cys-360 moves to the active site. Mutation of the Cys residue to Ala or Ser amino acid reduces the Kcat energy of the decarboxylation reaction drastically. Interestingly, ligand ZINC01703953 shown interaction with ODC protein, Lys-69 functional amino acid with docked score of -8.28 out of 35 ligands tested based on virtual screening (VS) with AutoDock suite in the current study. Another, top scoring (-9.69) ligand, ZINC67855534 is found to interact with amino acid residues, involved in the active site formation of the ODC enzyme from our current VS experiment. Hence, the ligands ZINC01703953 and ZINC67855534 could possibly consider as potential candidates against T. brucei upon further in-vitro experimental validations.