Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cells
The RAS protein is a notable target in cancer research, being the most often mutated oncogene in human malignancies. The RAS G12X mutation is predominantly found in non-small cell lung cancer, including G12C and G12S variants, which are associated with a poor prognosis. Despite the approval of two i...
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Elsevier
2025-01-01
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| author | Mansour S. Alturki Nada Tawfeeq Amal Alissa Zahra Ahbail Mohamed S. Gomaa Abdulaziz H. Al Khzem Thankhoe A. Rants'o Mohammad J. Akbar Waleed S. Alharbi Bayan Y. Alshehri Amjad N. Alotaibi Fahad A. Almughem Abdullah A. Alshehri |
| author_facet | Mansour S. Alturki Nada Tawfeeq Amal Alissa Zahra Ahbail Mohamed S. Gomaa Abdulaziz H. Al Khzem Thankhoe A. Rants'o Mohammad J. Akbar Waleed S. Alharbi Bayan Y. Alshehri Amjad N. Alotaibi Fahad A. Almughem Abdullah A. Alshehri |
| author_sort | Mansour S. Alturki |
| collection | DOAJ |
| description | The RAS protein is a notable target in cancer research, being the most often mutated oncogene in human malignancies. The RAS G12X mutation is predominantly found in non-small cell lung cancer, including G12C and G12S variants, which are associated with a poor prognosis. Despite the approval of two inhibitors for the KRAS G12C mutation (sotorasib and adagrasib), the necessity persists due to the emergence of resistance to these inhibitors, which has become a substantial concern. This work involved the repurposing of FDA-approved drugs through in silico methods to identify compounds capable of covalently binding to KRAS G12C (PDB entry: 6OIM) and G12S (PDB entry: 7TLG). The computational studies involved virtual screening, induced fit, and covalent docking, and molecular dynamics simulations, and identified five promising candidates, the antibiotics; capreomycin, cefadroxil, and Cefdinir, the antifungal; natamycin, and the anti-inflammatory, cortisone. The hits exhibited binding affinities between −9.98 and −11.35 kcal/mol compared to −9.81 for sotorasib and were found to be covalent binders targeting KRAS G12C and G12S. The computational results were supported with in vitro evaluation on A549 malignant cells and HFF-1 non-cancerous cells. The antiproliferative efficacy of these drugs was evaluated by MTS tests, and their IC50 values were determined in which natamycin, although non-selective, and cortisone showed the highest activity with IC50 of 53.42 and 53.51 μg/mL, respectively, followed by cefadroxil (84.63 μg/mL). This study promisingly repurposed five drugs for KRAS mutant lung cancer, of which cefadroxil, and cortisone are particularly warranting further assessment either as a standalone or combination therapy while capreomycin is still an effective inhibitor for KRAS G12C mutant as evident from in silico and in vitro studies. |
| format | Article |
| id | doaj-art-c749052be9d449348c64f37a4e35449d |
| institution | Kabale University |
| issn | 2352-9148 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Informatics in Medicine Unlocked |
| spelling | doaj-art-c749052be9d449348c64f37a4e35449d2025-01-11T06:41:38ZengElsevierInformatics in Medicine Unlocked2352-91482025-01-0152101612Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cellsMansour S. Alturki0Nada Tawfeeq1Amal Alissa2Zahra Ahbail3Mohamed S. Gomaa4Abdulaziz H. Al Khzem5Thankhoe A. Rants'o6Mohammad J. Akbar7Waleed S. Alharbi8Bayan Y. Alshehri9Amjad N. Alotaibi10Fahad A. Almughem11Abdullah A. Alshehri12Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam, 31441, Eastern Province, Kingdom of Saudi Arabia; Corresponding author.Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam, 31441, Eastern Province, Kingdom of Saudi Arabia; Corresponding author.College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi ArabiaCollege of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam, 31441, Eastern Province, Kingdom of Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam, 31441, Eastern Province, Kingdom of Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USADepartment of Pharmaceutics, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 34212, Saudi ArabiaDepartment of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi ArabiaAdvanced Diagnostics and Therapeutics Institute, Health Sector, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi ArabiaAdvanced Diagnostics and Therapeutics Institute, Health Sector, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi ArabiaAdvanced Diagnostics and Therapeutics Institute, Health Sector, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi ArabiaAdvanced Diagnostics and Therapeutics Institute, Health Sector, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi ArabiaThe RAS protein is a notable target in cancer research, being the most often mutated oncogene in human malignancies. The RAS G12X mutation is predominantly found in non-small cell lung cancer, including G12C and G12S variants, which are associated with a poor prognosis. Despite the approval of two inhibitors for the KRAS G12C mutation (sotorasib and adagrasib), the necessity persists due to the emergence of resistance to these inhibitors, which has become a substantial concern. This work involved the repurposing of FDA-approved drugs through in silico methods to identify compounds capable of covalently binding to KRAS G12C (PDB entry: 6OIM) and G12S (PDB entry: 7TLG). The computational studies involved virtual screening, induced fit, and covalent docking, and molecular dynamics simulations, and identified five promising candidates, the antibiotics; capreomycin, cefadroxil, and Cefdinir, the antifungal; natamycin, and the anti-inflammatory, cortisone. The hits exhibited binding affinities between −9.98 and −11.35 kcal/mol compared to −9.81 for sotorasib and were found to be covalent binders targeting KRAS G12C and G12S. The computational results were supported with in vitro evaluation on A549 malignant cells and HFF-1 non-cancerous cells. The antiproliferative efficacy of these drugs was evaluated by MTS tests, and their IC50 values were determined in which natamycin, although non-selective, and cortisone showed the highest activity with IC50 of 53.42 and 53.51 μg/mL, respectively, followed by cefadroxil (84.63 μg/mL). This study promisingly repurposed five drugs for KRAS mutant lung cancer, of which cefadroxil, and cortisone are particularly warranting further assessment either as a standalone or combination therapy while capreomycin is still an effective inhibitor for KRAS G12C mutant as evident from in silico and in vitro studies.http://www.sciencedirect.com/science/article/pii/S2352914824001692CapreomycinCortisone acetateCefdinirCefadroxilNatamycinKRAS |
| spellingShingle | Mansour S. Alturki Nada Tawfeeq Amal Alissa Zahra Ahbail Mohamed S. Gomaa Abdulaziz H. Al Khzem Thankhoe A. Rants'o Mohammad J. Akbar Waleed S. Alharbi Bayan Y. Alshehri Amjad N. Alotaibi Fahad A. Almughem Abdullah A. Alshehri Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cells Informatics in Medicine Unlocked Capreomycin Cortisone acetate Cefdinir Cefadroxil Natamycin KRAS |
| title | Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cells |
| title_full | Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cells |
| title_fullStr | Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cells |
| title_full_unstemmed | Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cells |
| title_short | Targeting KRAS G12C and G12S mutations in lung cancer: In silico drug repurposing and antiproliferative assessment on A549 cells |
| title_sort | targeting kras g12c and g12s mutations in lung cancer in silico drug repurposing and antiproliferative assessment on a549 cells |
| topic | Capreomycin Cortisone acetate Cefdinir Cefadroxil Natamycin KRAS |
| url | http://www.sciencedirect.com/science/article/pii/S2352914824001692 |
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