Computational aided mechanistic understanding of Camellia sinensis bioactive compounds against co-chaperone p23 as potential anticancer agent.

Co-chaperon p23 has been well established as molecular chaperon for the heat shock protein 90 (Hsp90) that further leads to immorality in cancer cells by providing defense against Hsp90 inhibitors, and as stimulating agent for generating overexpressed antiapoptotic proteins, that is, Hsp70 and Hsp27. The natural compounds such as catechins from Camellia sinensis (green tea) are also well known for inhibition activity against various cancer. However, molecular interaction profile and potential lead bioactive compounds against co-chaperon p23 from green tea are not yet reported. To this context, we study the various secondary metabolites of green tea against co-chaperon p23 using structure-based virtual screening from Traditional Chinese Medicine (TCM) database. Following 26 compounds were obtained from TCM database and further studied for extra precision molecular docking that showed binding score between -10.221 and -2.276 kcal/mol with co-chaperon p23. However, relative docking score to known inhibitors, that is, ailanthone (-4.54 kcal/mol) and gedunin ( 3.60 kcal/mol) along with ADME profile analysis concluded epicatechin (-7.013 kcal/mol) and cis-theaspirone (-4.495 kcal/mol) as potential lead inhibitors from green tea against co-chaperone p23. Furthermore, molecular dynamics simulation and molecular mechanics generalized born surface area calculations validated that epicatechin and cis-theaspirone have significantly occupied the active region of co-chaperone p23 by hydrogen and hydrophobic interactions with various residues including most substantial amino acids, that is, Thr90, Ala94, and Lys95. Hence, these results supported the fact that green tea contained potential compounds with an ability to inhibit the cancer by disrupting the co-chaperon p23 activity.

Hsp90 Co-chaperone p23 contributes to dopaminergic mitochondrial stress via stabilization of PHD2: Implications for Parkinson's disease.

The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotypes linked to Parkinson's disease (PD) and its inhibition is neuroprotective in disease models. Hsp90 is conventionally believed to act by suppressing induction of hsp70. Here, we report a novel hsp70-independent mechanism by which Hsp90 may also contribute to PD-associated neuropathology. We previously reported that inhibition of the enzyme prolyl hydroxylase domain 2 (PHD2) in conjunction with increases in hypoxia-inducible factor 1 alpha (HIF1α) results in protection of vulnerable dopaminergic substantia nigra pars compacta (DAergic SNpc) neurons in in vitro and in vivo models of PD. We discovered an increased interaction between PHD2 and the p23:Hsp90 chaperone complex in response to mitochondrial stress elicited by the mitochondrial neurotoxin 1-methyl-4-phenylpyridine (MPP+) within cultured DAergic cells. Genetic p23 knockdown was found to result in decreases in steady-state PHD2 protein and activity and reduced susceptibility to MPP+ neurotoxicity. Administration of the p23 inhibitor gedunin was also neuroprotective in these cells as well as in human induced pluripotent stem cell (iPSC)-derived neurons. Our data suggests that mitochondrial stress-mediated elevations in PHD2 interaction with the p23-hsp90 complex have detrimental effects on the survival of DAergic neurons, while p23 inhibition is neuroprotective. We propose that neurotoxic effects are tied to enhanced PHD2 stabilization by the hsp90-p23 chaperone complex that is abrogated by p23 inhibition. This demonstrates a novel connection between two independent pathways previously linked to PD, hsp90 and PHD2-HIF1α, which could have important implications for here-to-fore unexplored mechanisms underlying PD neuropathology.