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Design and Pharmacophore Study of Triazole Analogues as Aromatase Inhibitors
1School of Pharmaceutical Sciences, Guru Ghasidas Central University, Bilaspur, 495009 (C.G.) India.
Background:
In current scenario breast cancer measured as one of the dangerous health issues. An effective therapeutic class of drug known as aromatase inhibitors (AIs) is dominant against estrogen receptorpositive breast cancer. However, there is an urgent need to create target-specific AIs with better anti-breast cancer profiles due to the increased toxicity and adverse effects related to currently existing anti-breast cancer drugs.
Objectives:
In the present study, we have designed of 100 novel tiazole analogues as aromatase inhibitors their pharmacophoric features were explored.
Method:
Molecular docking was applied to a series of 4-substituted-1, 2, 3-triazoles containing letrozole for their aromatase inhibitory effects. The aromatase inhibitory activity of the compound in a series varies in the range of (IC50 = 0.008-31.26 μM). A hydrogen atom positioned at R1 of the triazole ring in compound (01) was responsible for the most potent compound (IC50 = 0.008 μM) in the series of 28 compounds as compared to letrozole. The self-organizing molecular field study was used to assess the molecular characteristics and biological activities of the compounds. The four models were developed using PLS and MLR methods. The PLS method was good for statistical analysis. The letrozole scaffold-based 100 compounds were designed by selecting an effective pharmacophore responsible for aromatase inhibitory activity. The designed compound was placed on the previous model as a test set, and its IC50 values were calculated.
Result:
Hydrogen bonds were established between the potent molecule (01) and the essential residues Met 374 and Arg 115, which were responsible for the aromatase-inhibiting action. Cross-validated q2 (0.6349) & noncross- validated r2 (0.7163) were discovered in the statistical findings as having reliable predictive power. Among 100 designed compounds, seven compounds showed good aromatase inhibitory activities.
Conclusion:
The additional final SOMFA model created for the interactions between the aromatase and the triazole inhibitors may be helpful for future modification and enhancement of the inhibitors of this crucial enzyme.
Insights
Researchers designed 100 novel triazole analogues as aromatase inhibitors to combat breast cancer. Compound 01 demonstrated potent activity, showing promise for developing targeted therapies with reduced toxicity.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Computational Chemistry
Background:
- Breast cancer remains a significant global health concern.
- Aromatase inhibitors (AIs) are crucial for treating estrogen receptor-positive breast cancer.
- Existing AIs have limitations, necessitating the development of novel, targeted agents with improved safety profiles.
Purpose of the Study:
- To design and explore pharmacophoric features of 100 novel triazole analogues as potential aromatase inhibitors.
- To identify potent compounds with enhanced anti-breast cancer activity.
- To investigate structure-activity relationships for optimizing AI design.
Main Methods:
- Utilized molecular docking to evaluate aromatase inhibitory effects of 4-substituted-1,2,3-triazoles.
- Employed self-organizing molecular field analysis (SOMFA) to assess molecular characteristics and biological activity.
- Developed predictive models using Partial Least Squares (PLS) and Multiple Linear Regression (MLR) methods.
Main Results:
- Identified compound 01 as the most potent inhibitor (IC50 = 0.008 μM), surpassing letrozole.
- Established key hydrogen bonds between compound 01 and aromatase residues Met 374 and Arg 115.
- Achieved reliable predictive power with cross-validated q2 (0.6349) and non-cross-validated r2 (0.7163).
- Seven out of 100 designed compounds exhibited significant aromatase inhibitory activity.
Conclusions:
- The developed SOMFA model provides insights into aromatase-triazole inhibitor interactions.
- Findings support the potential for future modifications to enhance triazole-based aromatase inhibitors.
- The study contributes to the development of targeted therapies for breast cancer with potentially reduced side effects.
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