The discovery and development of heat shock protein 70 (Hsp70) inhibitors represents a relatively new hot topic in cancer.  Recently, it has been shown that new pharmacophores from the class of 2,5'-thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and 3-(phenylthio)pyridines could selectively interact with a an allosteric pocket in Hsp70 (Taldone T. et al., J Med Chem. 2014 Feb 27;57(4):1208-242014).  We further took advantage of the validation of Hsp-70 as a promising target in anti-cancer research and perform an in silico HTS screening of the purchasable compounds of the ZINC database using the Pharmer-pharmacophore search technology provided by the ZINCPharmer (http://zincpharmer.csb.pitt.edu) online interface.  Many parameters provided by the filtering screen in ZINCPharmer (such as selective hydrophobic, aromatic, acceptor/donor of hydrogen-bonds and MW functions) were rationally changed to generate new libraries containing ZINC compounds potential active site directed inhibitors of Hsp-70.  The new discovered pharmacophore libraries were further imported as sdf files into the AutoDockVina and the rigid molecular docking was performed using different target X-ray available structures of Hsp-70: 1S3X, 2KHO, and 2P32.pdb.  The compounds predicted to have free energies of interaction lower than �-9 kcal/mol� and lacking the ADP-like conformation were further selected for the in vitro validation of their putative reversible competitive inhibition of Hsp-70 ATP-ase activity.   N-{(1R*,3S*)-3-[(cyclobutylamino)carbonyl]cyclopentyl}-2-(1H-1,2,4-triazol-3-yl)benzamide, 5-[(ketoBLAHyl)methylene]-2-thioxo-hexahydropyrimidine-4,6-quinone, N-(1-cycloheptyl-5-oxopyrrolidin-3-yl)-2-(1H-imidazol-2-yl)benzamide, [(3-chloro-4-fluorophenyl)amino]-N-[7-(4-methylpiperazinyl)benzo[2,3-c]1,2,5-o xadiazol-4-yl]carboxamide  are some of the new ZINC compounds found to be potential active-site directed Hsp-70 inhibitors and are predicted to have one digit nM Ki (inhibitory constants).

Discovery of new active site directed reversible inhibitors of Hsp-70 using a combination of pharmacophore searching with <i>ZINCPharmer</i> of the ZINC database and <i>AutoDock Vina</i> molecular docking

248th National Meeting (2014)

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Discovery of new active site directed reversible inhibitors of Hsp-70 using a combination of pharmacophore searching with ZINCPharmer of the ZINC database and AutoDock Vina molecular docking