In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules
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 modell...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/4/1103 |
| _version_ | 1797395984166158336 |
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| author | Serena Vittorio Rosaria Gitto Ilenia Adornato Emilio Russo Laura De Luca |
| author_facet | Serena Vittorio Rosaria Gitto Ilenia Adornato Emilio Russo Laura De Luca |
| author_sort | Serena Vittorio |
| collection | DOAJ |
| description | 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 ΔG<sub>bind</sub> 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. |
| first_indexed | 2024-03-09T00:43:44Z |
| format | Article |
| id | doaj.art-7405ea4e18ce44e7bf6bda4bed2aa274 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T00:43:44Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-7405ea4e18ce44e7bf6bda4bed2aa2742023-12-11T17:40:52ZengMDPI AGMolecules1420-30492021-02-01264110310.3390/molecules26041103In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small MoleculesSerena Vittorio0Rosaria Gitto1Ilenia Adornato2Emilio Russo3Laura De Luca4Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, ItalyScience of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, Viale Europa e Germaneto, I-88100 Catanzaro, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, ItalyComputer 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 ΔG<sub>bind</sub> 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.https://www.mdpi.com/1420-3049/26/4/1103mTORmolecular dynamics simulationternary complex FKBP12-rapamycin-FRBmolecular docking and structure-based virtual screeningpharmacophore modeling |
| spellingShingle | Serena Vittorio Rosaria Gitto Ilenia Adornato Emilio Russo Laura De Luca In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules Molecules mTOR molecular dynamics simulation ternary complex FKBP12-rapamycin-FRB molecular docking and structure-based virtual screening pharmacophore modeling |
| title | In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules |
| title_full | In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules |
| title_fullStr | In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules |
| title_full_unstemmed | In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules |
| title_short | In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules |
| title_sort | in silico strategy for targeting the mtor kinase at rapamycin binding site by small molecules |
| topic | mTOR molecular dynamics simulation ternary complex FKBP12-rapamycin-FRB molecular docking and structure-based virtual screening pharmacophore modeling |
| url | https://www.mdpi.com/1420-3049/26/4/1103 |
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