Targeting Heat Shock Proteins 60 and 70 of Toxoplasma gondii as a Potential Drug Target: In Silico Approach

Abstract

Heat shock proteins (Hsps) 60 and 70 are postulated as a potential drug target for toxoplasmosis due to its importance in the developmental and survival of Toxoplasma gondii (T. gondii). As of today, there have been no reports on three-dimensional (3D) structure of Hsp60 and Hsp70 deposited in the Brookhaven Protein Data Bank. Hence, this study was conducted to predict 3D structures for Hsp60 and Hsp70 in T. gondii by homology modeling. Selection of the best predicted model was done based on multiple scoring functions. In addition, virtual screening was performed to short-list chemical compounds from the National Cancer Institute (NCI) Diversity Set III in search of potential inhibitor against Hsp60 and Hsp70 in T. gondii. Prior to virtual screening, binding sites of Hsp60 and Hsp70 were predicted using various servers and were used as the center in docking studies. The Hsps were docked against known natural ligands to validate the method used in estimating free energy of binding (FEB) and possible interactions between ligand and protein. Virtual screening was performed with a total of 1560 compounds from the NCI Diversity Set III. The compounds were ranked subsequently according to their FEB. Molecular basis of interactions of the top five ranked compounds was investigated using Ligplot. The major interactions exhibited were hydrogen bonding and hydrophobic interactions in binding to Hsp60 and Hsp70. The results obtained provided information and guidelines for the development of inhibitors for Hsp60 and Hsp70 in T. gondii.

A Review on the Prevalence of Toxoplasma gondii in Humans and Animals Reported in Malaysia from 2008–2018

“…These antigens included the excretory–secretory antigens (ESA), surface antigens (SAG1, SAG2), rophtry antigens (ROP1, ROP8), and dense granule proteins (GRA2, GRA5, GRA7). The results obtained from works on the improved methods for diagnosis varied among the laboratories [ 27 , 52 , 54 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. They reported different levels of sensitivities and specificities of these markers.…”

“…The results obtained in the different research works reporting on the pathogenesis, immunogenicity, and treatment of T. gondii are worthy to be contextualized. The articles relative to Malaysia indicated some suitable proteins markers that can serve either for treatment or as good candidates for vaccine development [ 70 , 71 , 72 , 77 , 83 , 84 ]. Additionally, the fact that some of the drugs for the treatment of T. gondii are teratogenic and still no cure for the bradyzoite tissue cysts must be taken into consideration.…”

Observations on bradyzoite biology

“…Likewise, TgHsp70 expression is upregulated in alkaline conditions (tested in the Type II ME49 strain) and localizes to the parasite cytoplasm, similar to BAG1 [64]. Recently, the 3D structures of TgHsp60 and 70 were predicted based on homology modeling, which might aid in the development of drugs against these Toxoplasma gondii heat shock proteins [68]. Another cytoplasmic heat shock protein, TgHsp90, has increased expression under alkaline conditions and localizes to the nucleus and cytoplasm in bradyzoites [69].…”

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

“…TgHsp60 is essential for parasite survival and is involved in regulating the respiratory pathway of the parasite and its various development stages [138]. Inhibitors targeting T. gondii Hsp60 were identified using in silico modeling [139]. Using the same approach, a small molecule inhibitor that attaches to the ATP binding domain of TgHsp60 was identified, although experimental evidence for this is pending [139].…”

“…Inhibitors targeting T. gondii Hsp60 were identified using in silico modeling [139]. Using the same approach, a small molecule inhibitor that attaches to the ATP binding domain of TgHsp60 was identified, although experimental evidence for this is pending [139].…”