Current medicinal chemistry · 2026
Ligand and Structure-Based Drug Design of Biphenyl 1,2,4-Triazole Derivatives as Dual Target Inhibitors of Aromatase and Steroidal Sulfatase as Anti-Breast Cancer Agents.
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Vivekananthan G, Subramaniam Varun Sankar Siva, Sruthi N J Sai, Jayashree M, Dinesh Basavana Gowda Hosur, Ganjipette Srinivas, Kuppusamy Sujatha, Suresh A Jerad, Jaikanth C, Radhakrishnan Srimathi
Аннотация
INTRODUCTION: Dual inhibitors of AROM and STS (DASIs), through their synergistic action, hold the potential to suppress estrogen biosynthesis at multiple points. It also overcomes limitations associated with single-enzyme inhibition and reduces the risk of resistance development. In order to potentially improve the clinical outcomes in hormone-dependent breast cancers, 1,2,4-triazole derivatives having similar structural characteristics to third-generation Aromatase Inhibitors (AIs), including exemestane, letrozole, and anastrozole, were subjected to ligand-based screening. This research study comparatively analyzes the drug candidates as DASIs that aim at the development of advanced therapeutic strategies for breast cancer treatment.
MATERIALS AND METHODS: In this study, a set of 172 biphenyl 1,2,4-triazole derivatives with defined biological activity against AROM and STS enzymes was subjected to 3DQSAR modelling, followed by ADMET, molecular docking, and dynamics.
RESULTS: Through 3D-QSAR, significant statistical parameters of aromatase (q2 = 0.8429, r2 = 0.8874, r2pred = 0.8252) and steroidal sulfatase (q2 = 0.8877, r2 = 0.9402, r2pred = 0.9376) indicated the accuracy and reliability, and the good prediction power of the model. The external validation set further demonstrated its predictive capability. Furthermore, molecular docking, along with molecular dynamics at a time period of 100 ns, elucidated the stability of the docked complexes and found that Compound 109 emerged as the most promising dual inhibitor, exhibiting high binding affinities of -9.94 kcal/mol for Aromatase (AROM) and -9.41 kcal/mol for Steroid Sulfatase (STS). These values reflect a strong potential for dual enzyme inhibition.
DISCUSSION: The structural features of triazole derivatives through QSAR modelling established a statistical correlation, establishing a relationship between functional groups and their biological activity. They are found to have dual inhibition efficiency in a target-based approach, accelerating for synthetic accessibility.
CONCLUSION: The study highlights the potential of triazole derivatives and provides a multi-targeted therapeutic avenue for hormone-dependent breast cancers. It shows strong reliability and predictive power through molecular docking and a dynamic approach. Compound 109 emerged as the lead candidate due to its strong binding affinities and stable dual interactions.
MATERIALS AND METHODS: In this study, a set of 172 biphenyl 1,2,4-triazole derivatives with defined biological activity against AROM and STS enzymes was subjected to 3DQSAR modelling, followed by ADMET, molecular docking, and dynamics.
RESULTS: Through 3D-QSAR, significant statistical parameters of aromatase (q2 = 0.8429, r2 = 0.8874, r2pred = 0.8252) and steroidal sulfatase (q2 = 0.8877, r2 = 0.9402, r2pred = 0.9376) indicated the accuracy and reliability, and the good prediction power of the model. The external validation set further demonstrated its predictive capability. Furthermore, molecular docking, along with molecular dynamics at a time period of 100 ns, elucidated the stability of the docked complexes and found that Compound 109 emerged as the most promising dual inhibitor, exhibiting high binding affinities of -9.94 kcal/mol for Aromatase (AROM) and -9.41 kcal/mol for Steroid Sulfatase (STS). These values reflect a strong potential for dual enzyme inhibition.
DISCUSSION: The structural features of triazole derivatives through QSAR modelling established a statistical correlation, establishing a relationship between functional groups and their biological activity. They are found to have dual inhibition efficiency in a target-based approach, accelerating for synthetic accessibility.
CONCLUSION: The study highlights the potential of triazole derivatives and provides a multi-targeted therapeutic avenue for hormone-dependent breast cancers. It shows strong reliability and predictive power through molecular docking and a dynamic approach. Compound 109 emerged as the lead candidate due to its strong binding affinities and stable dual interactions.