Background: Human African trypanosomiasis is a fatal disease prevalent in approximately
36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious
cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase
is an enzyme of Trypanosoma brucei.
Methods: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival
in the human host. The success of finding a potent inhibitor in structure-based drug design lies
within the ability of computational tools to efficiently and accurately dock a ligand into the binding
cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei
pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various
drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean
Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These
clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several
factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred.
Results: The online server was used to analyze the side chain flexibility and four proteins were selected
on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds,
and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated
for the proteins and scoring functions. The best scoring function was used to understand the ligand
protein interactions with top common compounds of four proteins. In addition, we made a 3D
structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm-
PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational
drug design against these two human parasites.
Conclusion: The results indicated that relying just on re-docking and cross-docking experiments for
virtual screening of libraries isn’t enough and results might be misleading. Hence it has been suggested
that small scale virtual screening should be performed prior to large scale screening.