Title:A QSAR Study of Peptidyl Vinyl Sulfone Cysteine Protease Inhibitors Using Topomer CoMFA and Molecular Docking
Volume: 18
Issue: 8
Author(s): W.U. Lu-Yang, M.A. Yang-Min*, L.E.I. Shan, Wang Tian-Hao and Feng Yi
Affiliation:
- College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an 710021,China
Keywords:
Quantitative Structure-Activity Relationship (QSAR), peptidyl vinyl sulfone cysteine protease inhibitors, topomer
CoMFA, Topomer search, new drug design, molecular docking.
Abstract:
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 are 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.
Materials and 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 (r2), the interaction validation coefficient (q2) and the
external validation (r2
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 is higher than the 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 3D-QSAR 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.
