Computational modeling of the heat shock protein HSP90 alpha and a search for its small molecule inhibitors
keywords HEAT SHOCK PROTEIN, MOLECULAR DOCKING, MOLECULAR DYNAMICS, RATIONAL DRUG DESIGN
Reference persons MARCO AGOSTINO DERIU, JACEK ADAM TUSZYNSKI
External reference persons Dr. Maral Aminpour, Department of Biomedical Engineering, University of Alberta, Edmonton, Canada
Research Groups 28- biomedica
Thesis type COMPUTATIONAL
Description Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs. The overall structure of Hsp90 is similar to that of other proteins in that it contains all of the common secondary structural elements (i.e., alpha helixes, beta pleated sheets, and random coils). HSP90 is globular in structure, that is largely non-polar on the inside and polar on the outside, so as to be dissolved by water. Hsp90 contains nine helices and eight anti-parallel beta pleated sheets, which combine to form several alpha/beta sandwiches. The 3-10 helices make up approximately 11% of the protein's amino acid residues, which is much higher than the average 4% in other proteins. The project will focus on creating an equilibrated model of this protein under conditions typical of cancer cells. There are numerous PDB structures of HSP90, which will be used for this purpose. Also, there are various known inhibitors, for example: There are a number of existing drugs for this target we could investigate:
a) Rifabutin by Pharmacia & Upjohn
b) Geldanamycin by Kosan Sa Biosciences (acquired by BMS)
c) Alvespimycin and Tanespimycin (antibiotics)
This will serve to: (a) demonstrate the mode of action of these compounds, (b) create a pharmacophore and (c) find similar compounds in the database ZINC to see if other inhibitors can have better pharmacological profiles.
Required skills molecular dynamics, docking, bioinformatic searches
Notes This project may take place in Canada, at the University of Alberta, with the joint supervision of Dr. Maral Aminpour. Given the changing situation via a vis COVID-19, travel to Canada is optional and it would have to involve a student who is doubly vaccinated against the COVID-19 virus.
Deadline 26/09/2022 PROPONI LA TUA CANDIDATURA