In silico identification of potential Hsp90 inhibitors via ensemble docking, DFT and molecular dynamics simulations
Creators: name: Rezvani, Saba
name: Ebadi, Ahmad
name: Razzaghi-Asl, Nima
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biophysics
subject: Biochemistry
subject: Medicine
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences

description: The molecular chaperone heat shock protein 90 (Hsp90) has emerged as one of the most exciting targets for anticancer drug development and Hsp90 inhibitors are potentially useful chemotherapeutic agents in cancer. Within the current study, Hsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 structure query to find similar compounds (≥ 78%). Obtained small molecules (<b>1</b>-<b>29</b>) with defined similarity cut-off were docked into ensemble of Hsp90-α NTDs. Docked complexes were ranked on the basis of binding modes and Gibbs free energies as Hsp90 binders (cut-off point; ΔG<sub>b</sub> ≤ −12 kcal/mol). Top-ranked compounds were subjected to energy decomposition analysis per residue of binding pocket via density functional theory (DFT) calculations in B3LYP level of theory. Subsequent MD simulations of the top-ranked complexes were performed for 100 ns to explore the stable binding modes during a reasonable period in explicit water. Results of molecular docking and intermolecular binding analysis indicated that H-bond, hydrophobic and salt bridge interactions were determinant forces in complex formation. Compounds <b>19</b> and <b>20</b> were well accommodated in binding pocket of Hsp90 via relatively varied conformations. It was revealed that Asn51 and Phe138 were key residues that interacted stably to <b>19</b> and <b>20</b>. Although primary mechanism of action for proposed molecules are unknown and yet to be explored, results of the present study revealed key structural features for future structure-guided optimization toward potent inhibitors of Hsp90-α NTD. HighlightsHsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 based structure query to afford potential enzyme inhibitors <b>19</b> and <b>20</b>.Quantum chemical calculations confirmed docking results and verified pivotal role of a conserved residues (Asn51, Leu103, Phe138 and Tyr139) in making effective hydrogen bonds.MD simulations of top-ranked docked derivatives revealed the achievement of stable binding modes with less conformational variation of <b>20</b> than <b>19</b> in the active site of Hsp90-α NTD.H-bond, hydrophobic contacts and salt bridge interactions were determinant forces in binding interactions of <i>in silico</i> hits.Resorcinol and isoxazole were important structural motifs of <i>in silico</i> hits in binding to the active site of Hsp90-α NTD. Hsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 based structure query to afford potential enzyme inhibitors <b>19</b> and <b>20</b>. Quantum chemical calculations confirmed docking results and verified pivotal role of a conserved residues (Asn51, Leu103, Phe138 and Tyr139) in making effective hydrogen bonds. MD simulations of top-ranked docked derivatives revealed the achievement of stable binding modes with less conformational variation of <b>20</b> than <b>19</b> in the active site of Hsp90-α NTD. H-bond, hydrophobic contacts and salt bridge interactions were determinant forces in binding interactions of <i>in silico</i> hits. Resorcinol and isoxazole were important structural motifs of <i>in silico</i> hits in binding to the active site of Hsp90-α NTD. Communicated by Ramaswamy H. Sarma