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Keywords = ternary complex FKBP12-rapamycin-FRB

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13 pages, 2908 KB  
Article
In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules
by Serena Vittorio, Rosaria Gitto, Ilenia Adornato, Emilio Russo and Laura De Luca
Molecules 2021, 26(4), 1103; https://doi.org/10.3390/molecules26041103 - 19 Feb 2021
Cited by 15 | Viewed by 4979
Abstract
Computer aided drug-design methods proved to be powerful tools for the identification of new therapeutic agents. We employed a structure-based workflow to identify new inhibitors targeting mTOR kinase at rapamycin binding site. By combining molecular dynamics (MD) simulation and pharmacophore modelling, a simplified [...] Read more.
Computer aided drug-design methods proved to be powerful tools for the identification of new therapeutic agents. We employed a structure-based workflow to identify new inhibitors targeting mTOR kinase at rapamycin binding site. By combining molecular dynamics (MD) simulation and pharmacophore modelling, a simplified structure-based pharmacophore hypothesis was built starting from the FKBP12-rapamycin-FRB ternary complex retrieved from RCSB Protein Data Bank (PDB code 1FAP). Then, the obtained model was used as filter to screen the ZINC biogenic compounds library, containing molecules derived from natural sources or natural-inspired compounds. The resulting hits were clustered according to their similarity; moreover, compounds showing the highest pharmacophore fit-score were chosen from each cluster. The selected molecules were subjected to docking studies to clarify their putative binding mode. The binding free energy of the obtained complexes was calculated by MM/GBSA method and the hits characterized by the lowest ΔGbind values were identified as potential mTOR inhibitors. Furthermore, the stability of the resulting complexes was studied by means of MD simulation which revealed that the selected compounds were able to form a stable ternary complex with FKBP12 and FRB domain, thus underlining their potential ability to inhibit mTOR with a rapamycin-like mechanism. Full article
(This article belongs to the Special Issue Computational Methods in Drug Design and Food Chemistry)
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