A QSAR study of peptidyl vinyl sulfone cysteine protease inhibitors using Topomer CoMFA and Molecular Docking

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 2 ), the interaction validation coefficient (q2 ) and the external validation (r 2 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.

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Cysteine Protease Inhibitors Block Toxoplasma gondii Microneme Secretion and Cell Invasion

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01059-06 ◽

2007 ◽

Vol 51 (2) ◽

pp. 679-688 ◽

Cited By ~ 37

Author(s):

Chin Fen Teo ◽

Xing Wang Zhou ◽

Matthew Bogyo ◽

Vern B. Carruthers

Keyword(s):

Toxoplasma Gondii ◽

Protease Inhibitors ◽

Cell Invasion ◽

Cysteine Protease ◽

Gliding Motility ◽

Host Cells ◽

Vinyl Sulfone ◽

Cysteine Protease Inhibitors ◽

Adhesive Proteins ◽

Phenyl Vinyl

ABSTRACT Toxoplasma gondii enters host cells via an active, self-driven process to fulfill its need for intracellular replication and survival. Successful host cell invasion is governed by sequential release of secretory proteins from three specialized organelles, including the micronemes, which contribute adhesive proteins necessary for parasite attachment and penetration. Cumulative evidence from studies of Trypanosoma species and malaria parasites has shown that cysteine protease inhibitors represent potent anti-parasitic agents capable of curing infections in vivo. In this study, we screened a series of selective cysteine protease inhibitors for their effects on T. gondii cell invasion. Two of these compounds, morpholinourea-leucyl-homophenolalaninyl-phenyl-vinyl-sulfone and N-benzoxycarbonyl-(leucyl)3-phenyl-vinyl-sulfone, impaired T. gondii invasion and gliding motility at low-micromolar concentrations. Unexpectedly, these inhibitors did not affect surface proteolysis of microneme products but instead impaired an earlier step by precluding the secretion of microneme-derived adhesins to the parasite surface. Our findings suggest that cysteine protease activity is required for microneme secretion and cell invasion by T. gondii.

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Cysteine Protease Inhibitors Cure an Experimental Trypanosoma cruzi Infection

Journal of Experimental Medicine ◽

10.1084/jem.188.4.725 ◽

1998 ◽

Vol 188 (4) ◽

pp. 725-734 ◽

Cited By ~ 264

Author(s):

Juan C. Engel ◽

Patricia S. Doyle ◽

Ivy Hsieh ◽

James H. McKerrow

Keyword(s):

Trypanosoma Cruzi ◽

Protease Inhibitors ◽

Chagas Disease ◽

Golgi Complex ◽

Cysteine Protease ◽

Parasitic Infection ◽

Host Cells ◽

Vinyl Sulfone ◽

Cysteine Protease Inhibitors ◽

Lethal Infection

Trypanosoma cruzi is the causative agent of Chagas' disease. The major protease, cruzain, is a target for the development of new chemotherapy. We report the first successful treatment of an animal model of Chagas' disease with inhibitors designed to inactivate cruzain. Treatment with fluoromethyl ketone–derivatized pseudopeptides rescued mice from lethal infection. The optimal pseudopeptide scaffold was phenylalanine-homophenylalanine. To achieve cure of infection, this pseudopeptide scaffold was incorporated in a less toxic vinyl sulfone derivative. N-methyl piperazine-Phe-homoPhe-vinyl sulfone phenyl also rescued mice from a lethal infection. Six of the treated mice survived over nine months, three without further treatment. Three mice that had entered the chronic stage of infection were retreated with a 20-d regimen. At the conclusion of the experiments, five of the six mice had repeated negative hemacultures, indicative of parasitological cure. Studies of the effect of inhibitors on the intracellular amastigote form suggest that the life cycle is interrupted because of inhibitor arrest of normal autoproteolytic cruzain processing at the level of the Golgi complex. Parasites recovered from the hearts of treated mice showed the same abnormalities as those treated in vitro. No abnormalities were noted in the Golgi complex of host cells. This study provides proof of concept that cysteine protease inhibitors can be given at therapeutic doses to animals to selectively arrest a parasitic infection.

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