Computational Analysis of Azole Derivatives Targeting the PI3K/AKT/mTOR Pathway With In Vitro Cytotoxicity and Autophagy Evaluation.
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| Main Authors: | , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
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Journal of biochemical and molecular toxicology
2026
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| author | Regurajan, Rathika Poomani, Merlin Sobia Mariappan, Iyyadurai Subramanian, Venkatesh Sankar, Muthumanickam Pandi, Boomi Muthan, Krishnaveni |
| author_facet | Regurajan, Rathika Poomani, Merlin Sobia Mariappan, Iyyadurai Subramanian, Venkatesh Sankar, Muthumanickam Pandi, Boomi Muthan, Krishnaveni Regurajan, Rathika Poomani, Merlin Sobia Mariappan, Iyyadurai Subramanian, Venkatesh Sankar, Muthumanickam Pandi, Boomi Muthan, Krishnaveni |
| collection | PubMed - marine biology |
| contents | Computational Analysis of Azole Derivatives Targeting the PI3K/AKT/mTOR Pathway With In Vitro Cytotoxicity and Autophagy Evaluation. Regurajan, Rathika Poomani, Merlin Sobia Mariappan, Iyyadurai Subramanian, Venkatesh Sankar, Muthumanickam Pandi, Boomi Muthan, Krishnaveni TOR Serine-Threonine Kinases Humans Proto-Oncogene Proteins c-akt Autophagy Phosphatidylinositol 3-Kinases Molecular Docking Simulation Signal Transduction Cell Line, Tumor Molecular Dynamics Simulation Azoles Antineoplastic Agents This study aims to identify potential azole-derived inhibitors targeting the PI3K/AKT/mTOR signaling pathway involved in autophagy regulation and cancer progression. A structure-based virtual screening approach was employed using molecular docking, molecular dynamics (MD) simulations, and free energy calculations (MMGBSA and MMPBSA). The pharmacokinetic profiles and toxicity of lead compounds were assessed using ADMET analysis. In vitro validation was performed using MTT and MDC staining assays on MDA-MB-231 breast cancer cells.Among the screened compounds, KR4 demonstrated strong binding affinity towards all three kinases (-8.289, -5.222, and -6.331 kcal/mol) respectively with favorable pharmacokinetic properties. MD simulation confirmed the stability of the KR4-protein complexes, while post-MD MMPBSA analysis validated the binding energetics. In vitro studies revealed dose-dependent cytotoxicity of KR4 (IC₅₀ ≈ 39 µM) and induction of autophagy in treated cells. The integration of in silico and in vitro approaches highlights KR4 as a promising multi-target inhibitor of the PI3K/AKT/mTOR pathway with potential anti-cancer properties. These findings support further exploration of KR4 for therapeutic development. |
| format | Artículo científico |
| id | pubmed_42021531 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Journal of biochemical and molecular toxicology |
| record_format | pubmed |
| spellingShingle | Computational Analysis of Azole Derivatives Targeting the PI3K/AKT/mTOR Pathway With In Vitro Cytotoxicity and Autophagy Evaluation. Regurajan, Rathika Poomani, Merlin Sobia Mariappan, Iyyadurai Subramanian, Venkatesh Sankar, Muthumanickam Pandi, Boomi Muthan, Krishnaveni TOR Serine-Threonine Kinases Humans Proto-Oncogene Proteins c-akt Autophagy Phosphatidylinositol 3-Kinases Molecular Docking Simulation Signal Transduction Cell Line, Tumor Molecular Dynamics Simulation Azoles Antineoplastic Agents Computational Analysis of Azole Derivatives Targeting the PI3K/AKT/mTOR Pathway With In Vitro Cytotoxicity and Autophagy Evaluation. Regurajan, Rathika Poomani, Merlin Sobia Mariappan, Iyyadurai Subramanian, Venkatesh Sankar, Muthumanickam Pandi, Boomi Muthan, Krishnaveni TOR Serine-Threonine Kinases Humans Proto-Oncogene Proteins c-akt Autophagy Phosphatidylinositol 3-Kinases Molecular Docking Simulation Signal Transduction Cell Line, Tumor Molecular Dynamics Simulation Azoles Antineoplastic Agents This study aims to identify potential azole-derived inhibitors targeting the PI3K/AKT/mTOR signaling pathway involved in autophagy regulation and cancer progression. A structure-based virtual screening approach was employed using molecular docking, molecular dynamics (MD) simulations, and free energy calculations (MMGBSA and MMPBSA). The pharmacokinetic profiles and toxicity of lead compounds were assessed using ADMET analysis. In vitro validation was performed using MTT and MDC staining assays on MDA-MB-231 breast cancer cells.Among the screened compounds, KR4 demonstrated strong binding affinity towards all three kinases (-8.289, -5.222, and -6.331 kcal/mol) respectively with favorable pharmacokinetic properties. MD simulation confirmed the stability of the KR4-protein complexes, while post-MD MMPBSA analysis validated the binding energetics. In vitro studies revealed dose-dependent cytotoxicity of KR4 (IC₅₀ ≈ 39 µM) and induction of autophagy in treated cells. The integration of in silico and in vitro approaches highlights KR4 as a promising multi-target inhibitor of the PI3K/AKT/mTOR pathway with potential anti-cancer properties. These findings support further exploration of KR4 for therapeutic development. |
| title | Computational Analysis of Azole Derivatives Targeting the PI3K/AKT/mTOR Pathway With In Vitro Cytotoxicity and Autophagy Evaluation. |
| topic | TOR Serine-Threonine Kinases Humans Proto-Oncogene Proteins c-akt Autophagy Phosphatidylinositol 3-Kinases Molecular Docking Simulation Signal Transduction Cell Line, Tumor Molecular Dynamics Simulation Azoles Antineoplastic Agents |
| url | https://pubmed.ncbi.nlm.nih.gov/42021531/ |