Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines
Introduction: Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6. Methods: We designed and synthesized...
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Tabriz University of Medical Sciences
2024-07-01
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| Online Access: | https://bi.tbzmed.ac.ir/PDF/bi-14-29951.pdf |
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| author | Chaithra R Shetty C. S. Shastry Parasuraman P Srinivas Hebbar |
| author_facet | Chaithra R Shetty C. S. Shastry Parasuraman P Srinivas Hebbar |
| author_sort | Chaithra R Shetty |
| collection | DOAJ |
| description | Introduction: Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6. Methods: We designed and synthesized a range of substituted thiazolo-pyridopyrimidines (4a-p). Computational ADME/T analysis and molecular docking were performed using the crystal structure of CDK4/6. Subsequently, we synthesized the top-scoring compounds, characterized them using IR, NMR, and Mass spectroscopy, and assessed their impact on MCF-7 and MDAMB-231 cell lines using the SRB assay. To further evaluate stability, molecular dynamics simulations were conducted for the two most promising compounds within the binding site. Results: The docking scores indicated stronger interactions for compounds 4a, 4c, 4d, and 4g. As a result, these specific compounds (4a, 4c, 4d, and 4g) were chosen for synthesis and subsequent screening to assess their cytotoxic effects. Remarkably, compounds 4c and 4a exhibited the most promising activity in terms of their IC50 values across both tested cell lines. Furthermore, molecular dynamics simulation studies uncovered an elevated level of stability within the 4c- 6OQO complex. Conclusion: By integrating insights from computational, in vitro, and molecular dynamics simulation findings, compound 4c emerges as a leading candidate for future investigations. The presence of a polar hydroxyl group at the C2 position of the 8-phenyl substitution on the pyridopyrimidine rings appears to contribute to the heightened activity of the compound. Further enhancements to cytotoxic potential could be achieved through structural refinements. |
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| institution | Kabale University |
| issn | 2228-5652 2228-5660 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | Tabriz University of Medical Sciences |
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| series | BioImpacts |
| spelling | doaj-art-1cd9a289616b44cbb5566bb8bb16fbbf2025-01-18T10:00:03ZengTabriz University of Medical SciencesBioImpacts2228-56522228-56602024-07-01144299512995110.34172/bi.2023.29951bi-29951Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell linesChaithra R Shetty0C. S. Shastry1Parasuraman P2Srinivas Hebbar3Nitte Deemed to be University, NGSM Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Deralakatte, Mangaluru, Karnataka, India, 575018Nitte Deemed to be University, NGSM Institute of Pharmaceutical Sciences, Department of Pharmacology, Deralakatte, Mangaluru, Karnataka, India, 575018Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M S Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India, 560054Pharmaceutics Department, Manipal College of Pharmaceutical Sciences, MAHE, Manipal, Karnataka, India, 576104Introduction: Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6. Methods: We designed and synthesized a range of substituted thiazolo-pyridopyrimidines (4a-p). Computational ADME/T analysis and molecular docking were performed using the crystal structure of CDK4/6. Subsequently, we synthesized the top-scoring compounds, characterized them using IR, NMR, and Mass spectroscopy, and assessed their impact on MCF-7 and MDAMB-231 cell lines using the SRB assay. To further evaluate stability, molecular dynamics simulations were conducted for the two most promising compounds within the binding site. Results: The docking scores indicated stronger interactions for compounds 4a, 4c, 4d, and 4g. As a result, these specific compounds (4a, 4c, 4d, and 4g) were chosen for synthesis and subsequent screening to assess their cytotoxic effects. Remarkably, compounds 4c and 4a exhibited the most promising activity in terms of their IC50 values across both tested cell lines. Furthermore, molecular dynamics simulation studies uncovered an elevated level of stability within the 4c- 6OQO complex. Conclusion: By integrating insights from computational, in vitro, and molecular dynamics simulation findings, compound 4c emerges as a leading candidate for future investigations. The presence of a polar hydroxyl group at the C2 position of the 8-phenyl substitution on the pyridopyrimidine rings appears to contribute to the heightened activity of the compound. Further enhancements to cytotoxic potential could be achieved through structural refinements.https://bi.tbzmed.ac.ir/PDF/bi-14-29951.pdfthiazolo-pyridopyrimidinescdk4/6molecular dockingcytotoxicitymd simulation |
| spellingShingle | Chaithra R Shetty C. S. Shastry Parasuraman P Srinivas Hebbar Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines BioImpacts thiazolo-pyridopyrimidines cdk4/6 molecular docking cytotoxicity md simulation |
| title | Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines |
| title_full | Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines |
| title_fullStr | Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines |
| title_full_unstemmed | Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines |
| title_short | Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines |
| title_sort | thiazolo pyridopyrimidines an in silico evaluation as a lead for cdk4 6 inhibition synthesis and cytotoxicity screening against breast cancer cell lines |
| topic | thiazolo-pyridopyrimidines cdk4/6 molecular docking cytotoxicity md simulation |
| url | https://bi.tbzmed.ac.ir/PDF/bi-14-29951.pdf |
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