Background: Malaria is one of the most important infectious diseases in the world. The most severe form of
malaria in humans is caused by Plasmodium falciparum. Malaria is a worldwide health problem, with 214 million new cases
in 2015 and 438,000 deaths, most of which in Africa. Therefore, there is an urgent need for novel, low-toxic, more specific
inhibitors to find new antimalarial agents. A promising target for antimalarial drug design is falcipain-2, a cysteine protease
from P. falciparum, that has received considerable attention due to its key role in the life cycle of the parasite.
Methods: Three-dimensional quantitative structure-activity relationship (3D-QSAR) models of 39 peptidyl vinyl sulfone
cysteine protease inhibitors was constructed using Topomer CoMFA. Topomer Search was employed to virtually screen
lead-like compounds in the ZINC database. Molecular docking was employed to further explore the binding requirements
between the ligands and the receptor protein which included several hydrogen bonds between peptidyl vinyl sulfone
cysteine protease inhibitors and active site residues.
Results: The non-cross correlation coefficient (r
), the interaction validation coefficient (q2
) and the external validation
pred) were 0.902, 0.685 and 0.763, respectively. The results showed that the model not only had good estimation stability
but also good prediction capability. 22 new molecules were obtained, whose predicted activity are higher than template
molecules. The results showed that the Topomer Search technology can be effectively applied to screen and design new
peptidyl vinyl sulfone cysteine protease inhibitors. Molecular docking showed extensive interactions between peptidyl vinyl
sulfone cysteine protease inhibitors and residues of LYS24, ASP21, LYS59 and ASP17 in the active site.
Conclusion: 39 peptidyl vinyl sulfone cysteine protease inhibitors were used in the 3D-QSAR study. Topomer CoMFA 3DQSAR method was used to build the model, and the model was well predicted and statistically validated. The design of
potent new inhibitors of cysteine protease can get useful insights from these results.