Kanser tedavisi için HDAC6 ve alk'yi hedef alan ikili Hsp90 inhibitörlerinin in siliko keşfi

Heat shock protein 90 (Hsp90), histone deacetylase 6 (HDAC6), and anaplastic lymphoma kinase (ALK) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. Interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of Hsp90-HDAC6 or Hsp90-ALK can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers. The objective of this thesis was to explore potential compounds that can inhibit both Hsp90-HDAC6 and Hsp90-ALK proteins. Therefore, a number of in-silico computational techniques were employed. For the Hsp90-HDAC6 part, 791 molecules with similarity filtration from the ZINC database and 361,179 compounds with Lipinski rule of 5 criteria from the COCONUT database were selected for the Hsp90-ALK part. All of them were subjected to docking on responsible protein structures. The top ligands demonstrating the best binding scores against both targets, along with their references, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands. Upon completion of all analyses, a detailed in-silico evaluation revealed that ZINC27653366 and CNP0264442.1 exhibited the highest inhibitory potential for Hsp90-HDAC6 and Hsp90-ALK, respectively, making them the most promising inhibitors.