Selectivity Mechanism of Hsp90 Isoform Inhibition Through Computational Investigation

The Hsp90 family has been extensively studied as a promising target against cancer and neurodegenerative diseases due to its crucial role in protein maturation and transport. However, the toxic and side effects such as cardiotoxicity and ocular toxicity caused by the pan-inhibition of Hsp90 cannot be ignored. The development of highly selective inhibitors toward Hsp90 alpha over Grp94 has been proved to be a feasible approach to avoid these toxic and side effects. Therefore, to explore the different binding modes of inhibitors against Hsp90 alpha and Grp94, hybrid computational methods were used to demonstrate the interaction mechanism between selective inhibitors targeting Hsp90 alpha and Grp94. The results showed that hydrogen bond interaction and hydrophobicity are crucial for the selective inhibition of Hsp90 alpha, while Grp94 specificity mainly relies on a typical hydrophobic cavity. These findings would provide the theoretical basis for the future development of novel selective inhibitors of Hsp90 alpha and Grp94.