Identifying a C-terminal ATP binding sites-based novel Hsp90-Inhibitor in silico: a plausible therapeutic approach in Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD) is a progressive brain disorder, which gradually and irreversibly destroys the intellectual and cognitive abilities of the brain. Heat shock protein 90 (Hsp90α) is a molecular chaperone which was found to regulate the function of number of client proteins including tau that is involved in the cause of the AD. Inhibition of Hsp90α by C-Terminal domain (CTD) ATP binding-site blockage might be used as an effective treatment strategy against the disease via degradation of tau proteins that are involved in the progression of the disease. Till date, a variety of drugs have been identified as Hsp90α inhibitors, which include Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone. However, which drug among the four binds to the CTD ATP binding site strongly and what are the specific residue responsible for such binding, have not been reported so far.

Hypothesis: We hypothesize that binding site for ATP of Hsp90α CTD contains multiple ATP binding sites. We also hypothesize that a drug which can bind to the ATP binding site of CTD strongly can inhibit Hsp90α function which is in turn redirects towards the proteasomal degradation of diseased client protein like tau in AD. Such inhibition will find a novel therapeutic approach in the treatment of AD.

Experimental design: The identification of ATP binding site of Hsp90α CTD was done using various software tools like Hex 6.3, CastP, protein Hydrophobicity plots, ATPint and LigPlot+ v.1.4.5. Docking experiments were conducted between Hsp90αCTD and its inhibitors at these ATP binding site using the Autodock 4.0. The docking energies were further compared to obtain the most effective Hsp90α inhibitor of CTD.

Results: From our experiments, Leucine (Leu) 665, Leu 666 and Leu 694 were predicted to be located in CTD ATP binding site. Furthermore, docking studies were performed of various Hsp90α inhibitors like Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone with the previously recognized ATP binding residues of CTD i.e. Leu 665, Leu 666 and Leu 694. The docking results of Derrubone showed the highest binding energy at all the three sites of ATP interaction. Additionally, Derrubone showed the best binding energy at Leu 666 (-7.53kcal/mol) compared to Leu 665 (-7.20kcal/mol) and Leu 694 (-6.67kcal/mol).

Conclusion: Based on our findings, we propose that the recognized sites i.e. Leu665, Leu 666 and Leu694 could possibly be the binding sites of Hsp90α CTD for ATP and the Hsp90 inhibitors. It was predicted that Derrubone could bind with CTD of Hsp90α strongly and resulted tau protein degradation which might be considered to be a therapeutic approach in AD.