Computational modeling of the heat shock protein HSP90 alpha and a search for its small molecule inhibitors

Heat shock protein 90 (Hsp90) is a chaperone protein that protects proteins from heat stress, aids in the correct folding of other proteins and assists in protein degradation. It also stabilizes several proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs. The inhibition of Hsp90 causes cell death, as it induces the ubiquitin-proteasome system to eliminate the incorrectly folded proteins within the tumor cells, whose proliferation is induced by the inhibition of Hsp90. Another important role of Hsp90 in cancer is the stabilization of mutant proteins, it seems that Hsp90 can intervene to maintain the correct folding of the less stable proteins produced by DNA mutations, making the effect of these mutations phenotypically less relevant. It is also worth mentioning the implication of this protein in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and, according to recent discoveries, also in multiple sclerosis and in spinal and bulbar muscular atrophy. This project focuses on the creation of an equilibrated model of this protein under conditions typical of cancer cells and on the demonstration of the mode of action of some Hsp90 inhibitors. Investigating the chaperone using computational methodologies, specifically both molecular docking and molecular dynamics simulations, have proven to be valuable tools for exploring and fully understanding the binding between Hsp90 and these compounds. It was also important to find similar compounds in the ZINC database to see if other inhibitors could have better pharmacological profiles. All of this was made possible by the abundance of data on X-ray resolved crystallographic structures, which aided the work by making available the structures of many known inhibitors. This also has influenced the choice of a starting model complex, on which the molecular docking protocol was later based. Pharmacokinetic analysis carried out in this work, as well as the other strategies, are aimed at improving the efficacy of Hsp90 inhibitors to maximize the full potential of this pharmaceutical class.