@conference{
author = "Pajeva, Ilza and Tsakovska, Ivanka and Alov, Petko and Pencheva, Tania and Lessigiarskaa, Iglika and Dinić, Jelena and Podolski-Renić, Ana and Jovanović, Mirna and Musso, Loana and Dallavalle, Sabrina and Pešić, Milica",
year = "2020",
abstract = "Heat Shock Protein 90 (Hsp90) is an ATP-dependent molecular chaperone which interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents because of their limitations in physicochemical properties, safety profiles and efflux by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). In the efforts to develop dual targeting molecules with potential to act against both, deregulated cancer metabolism by Hsp90 inhibition and MDR mechanism by P-gp inhibition, eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in sensitive
and corresponding resistant cancer cells with P-gp overexpression [1]. Three compounds were identified as dual Hsp90 and P-gp inhibitors. This presentation describes in silico studies that were undertaken to elucidate possible interactions of the dual inhibitors with P-gp. In particular, docking simulations were performed using the recently resolved structures of the human P-gp extracted from Protein Data Bank (www.rcsb.org). These structures provide an excellent opportunity for comparison of substrate- and inhibitor-bound structures in the drug-binding cavity of P-gp [2]. Different docking protocols were compared and the one with the best performance on re-docking of the X-ray taxol and zosuquidar structures was selected in terms of: (i) similarity between the generated poses and the corresponding structures in the crystal complex, and (ii) calculated scores, that approximate the binding affinity. The P-gp-ligand interactions were analyzed to outline key residues potentially involved in binding. Based on the results, it was suggested that the binding sites of the studied compounds may partially overlap with a binding site of the P-gp substrate Rhodamine 123, implying that these compounds may act as its competitive inhibitors. The in silico results are in accordance with the experimental findings and contribute to the elucidation of the mechanism action of the dual inhibitors.",
publisher = "COST Action CA17104",
journal = "Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia",
title = "In silico study to elucidate possible interactions of Hsp90 inhibitors with P-gp",
pages = "49",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6498"
}
