Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies
Abstract VEGFR2 and FAK signaling pathways are interconnected and have synergistic effects on tumor angiogenesis, growth, and metastasis. Thus, instead of the conventional targeting of each of these proteins individually with a specific inhibitor, the present work aimed to discover novel dual inhibi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | BMC Chemistry |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13065-024-01130-5 |
| _version_ | 1797275981044514816 |
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| author | Marwa A. Fouad Alaa A. Osman Noha M. Abdelhamid Mai W. Rashad Ashrakat Y. Nabawy Ahmed M. El Kerdawy |
| author_facet | Marwa A. Fouad Alaa A. Osman Noha M. Abdelhamid Mai W. Rashad Ashrakat Y. Nabawy Ahmed M. El Kerdawy |
| author_sort | Marwa A. Fouad |
| collection | DOAJ |
| description | Abstract VEGFR2 and FAK signaling pathways are interconnected and have synergistic effects on tumor angiogenesis, growth, and metastasis. Thus, instead of the conventional targeting of each of these proteins individually with a specific inhibitor, the present work aimed to discover novel dual inhibitors targeting both VEGFR2 and FAK exploiting their association. To this end, receptor-based pharmacophore modeling technique was opted to generate 3D pharmacophore models for VEGFR2 and FAK type II kinase inhibitors. The generated pharmacophore models were validated by assessing their ability to discriminate between active and decoy compounds in a pre-compiled test set of VEGFR2 and FAK active compounds and decoys. ZINCPharmer web tool was then used to screen the ZINC database purchasable subset using the validated pharmacophore models retrieving 42,616 hits for VEGFR2 and 28,475 hits for FAK. Subsequently, they were filtered using various filters leaving 13,023 and 6,832 survived compounds for VEGFR2 and FAK, respectively, with 124 common compounds. Based on molecular docking simulations, thirteen compounds were found to satisfy all necessary interactions with VEGFR2 and FAK kinase domains. Thus, they are predicted to have a possible dual VEGFR2/FAK inhibitory activity. Finally, SwissADME web tool showed that compound ZINC09875266 is not only promising in terms of binding pattern to our target kinases, but also in terms of pharmacokinetic properties. |
| first_indexed | 2024-03-07T15:21:50Z |
| format | Article |
| id | doaj.art-58a6b9bddc3941c8a29a13e13b1ea8fb |
| institution | Directory Open Access Journal |
| issn | 2661-801X |
| language | English |
| last_indexed | 2024-03-07T15:21:50Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Chemistry |
| spelling | doaj.art-58a6b9bddc3941c8a29a13e13b1ea8fb2024-03-05T17:34:55ZengBMCBMC Chemistry2661-801X2024-02-0118112010.1186/s13065-024-01130-5Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studiesMarwa A. Fouad0Alaa A. Osman1Noha M. Abdelhamid2Mai W. Rashad3Ashrakat Y. Nabawy4Ahmed M. El Kerdawy5Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo UniversityPharmaceutical Chemistry Department, School of Pharmacy, Newgiza University (NGU), NewgizaPharmaceutical Chemistry Department, School of Pharmacy, Newgiza University (NGU), NewgizaPharmaceutical Chemistry Department, School of Pharmacy, Newgiza University (NGU), NewgizaPharmaceutical Chemistry Department, School of Pharmacy, Newgiza University (NGU), NewgizaPharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo UniversityAbstract VEGFR2 and FAK signaling pathways are interconnected and have synergistic effects on tumor angiogenesis, growth, and metastasis. Thus, instead of the conventional targeting of each of these proteins individually with a specific inhibitor, the present work aimed to discover novel dual inhibitors targeting both VEGFR2 and FAK exploiting their association. To this end, receptor-based pharmacophore modeling technique was opted to generate 3D pharmacophore models for VEGFR2 and FAK type II kinase inhibitors. The generated pharmacophore models were validated by assessing their ability to discriminate between active and decoy compounds in a pre-compiled test set of VEGFR2 and FAK active compounds and decoys. ZINCPharmer web tool was then used to screen the ZINC database purchasable subset using the validated pharmacophore models retrieving 42,616 hits for VEGFR2 and 28,475 hits for FAK. Subsequently, they were filtered using various filters leaving 13,023 and 6,832 survived compounds for VEGFR2 and FAK, respectively, with 124 common compounds. Based on molecular docking simulations, thirteen compounds were found to satisfy all necessary interactions with VEGFR2 and FAK kinase domains. Thus, they are predicted to have a possible dual VEGFR2/FAK inhibitory activity. Finally, SwissADME web tool showed that compound ZINC09875266 is not only promising in terms of binding pattern to our target kinases, but also in terms of pharmacokinetic properties.https://doi.org/10.1186/s13065-024-01130-5Pharmacophore modellingVirtual screeningMolecular dockingCancerFAKVEGFR2 |
| spellingShingle | Marwa A. Fouad Alaa A. Osman Noha M. Abdelhamid Mai W. Rashad Ashrakat Y. Nabawy Ahmed M. El Kerdawy Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies BMC Chemistry Pharmacophore modelling Virtual screening Molecular docking Cancer FAK VEGFR2 |
| title | Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies |
| title_full | Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies |
| title_fullStr | Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies |
| title_full_unstemmed | Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies |
| title_short | Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies |
| title_sort | discovery of dual kinase inhibitors targeting vegfr2 and fak structure based pharmacophore modeling virtual screening and molecular docking studies |
| topic | Pharmacophore modelling Virtual screening Molecular docking Cancer FAK VEGFR2 |
| url | https://doi.org/10.1186/s13065-024-01130-5 |
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