Identification and inhibition of C-terminal ATP-binding sites of Hsp90α through design of novel derrubone analogues as a plausible approach towards Alzheimer’s disease treatment

Abstract

The significant causative factors of Alzheimer's disease progression is the failure of the heat shock protein Hsp-90 to adequately refold the insoluble Tau protein tangles formed within the neuronal cytoplasm. A variety of drug molecules have been hitherto designed and tested for satisfactory insilico and invitro inhibition of the Hsp90 protein complex, rendering the cellular system to switch to proteasomal degradation pathway towards the tangled Tau elimination. Inhibition of C-Terminal of Hsp90á by blocking its ATP binding sites might be used as an effective therapeutic approach for the treatment of AD. In our present work, it was observed that Leu 666, Leu 666 and Leu 694 could possibly be the ATP binding sites of Hsp90á CTD. It was also known from the experimental results that Derrubone showed the best binding affinity (-7.53 kcal/mol) for Hsp90á CTD. Derrubone, has been structurally modified resulting in molecular analogues that have basic molecular skeleton of the original drug but serve improved ADME and inhibitory properties as against the same. Additionally, two previously experimentally synthesized Derrubone analogues developed by Blagg et. al. have been analyzed for validation of our recognized ATP binding sites and compared with the designed analogues for their inhibitory properties at the recently recognized ATP-binding sites of the Hsp-90 molecule. Analogue 26 consisting of ether substitution at the 5th position of the isoflavon backbone proved a better drug as compared to Derrubone and the analogues developed at the laboratory of Blagg et. al, with a binding energy of -10.16 kcal mol-1 at Leu694 binding site, inhibitory constant of 0.036 µM and lipophilicity of 4.481. It was concluded from the data obtained from experimental results that A26 could bind with CTD of Hsp90á strongly and result Tau protein degradation which might be considered to be a therapeutic approach in AD.