Molecular Dynamics Simulation For Hsp90and Research Of Its Inhibitors

Heat shock protein is molecular chaperone and highly conservative protein in thebiological evolution, which palys a significant part in life activity related to cellapoptosis, mature and transport client proteins. Hsp90has emerged as an excitingtarget for cancer treatment. This research has utilized molecular dynamics method tostudy the important waters and newly found active pocket S3of Hsp90, adoptedhomology modeling method to build the structure of human Hsp90, used autodockmethod to design the inhibitors.Firstly, the experiment utilized molecular dynamics method to study theN-domain of Hsp90, analyzed the interaction in the whole trajectory betweenN-domain of Hsp90and inhibitors, explored the contribution of constitution waters tomaintaining the conformation of protien structure and inhibitors, and studied how thenewly found active pocket S3changed. The result showed that Met98、Leu107、Phe138、Trp162、Asp93and Thr184were key residues to the interaction betweenprotein and inhibitors, Wat2137、Wat2262、Wat2059and Wat2134played animportant role in maintaining the stability of complex of protein and inhibitors, anddifferent types of inhibitors would have dismillar effects on the double-flab residuePhe138and Leu107of the active pocket.Based on the aboved research, the FBDD and autodock method were used toscreen the compound data bank and design the new inhibitors of Hsp90based on PU3scaffold. The result showed that compounds derived from splicing of L81and PYUwhich were extended to the active pocket S3, not meeting the experimentalexpectations. Compoud A4B4and A10B4derived from splicing of fragments thatoriginated from protein cystal had a good combinative mode with protein receptor.The design of inhibitors offered a new thought to study the drug for cancer treatment.In addition, the topic utilized homology modeling, autodock and moleculardynamics methods to study the binding sites of C-terminal domain of human Hsp90and inhibitors. Self-builded protien structure and reported inhibitors of C-terminaldomain of human Hsp90were used to predict the binding sites. Compounds derivedfrom Sigma-Aldrich chemical handbook were utilized to screen the potential leadcompounds of C-terminal domain of human Hsp90. The methods and conclusions of the research on Hsp90protein and inhibitorsprovided a theoretical reference for futher finding the new inhibitors which haddesired binding mode with protein receptor.