In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα)
Estrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modifie...
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2025-07-01
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| author | Dadang Muhammad Hasyim Ida Musfiroh Rudi Hendra Taufik Muhammad Fakih Nur Kusaira Khairul Ikram Muchtaridi Muchtaridi |
| author_facet | Dadang Muhammad Hasyim Ida Musfiroh Rudi Hendra Taufik Muhammad Fakih Nur Kusaira Khairul Ikram Muchtaridi Muchtaridi |
| author_sort | Dadang Muhammad Hasyim |
| collection | DOAJ |
| description | Estrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modified chalcone compounds into pyrazoline benzenesulfonamide derivatives (Modifina) which show activity as an ERα inhibitor. This study aimed to design novel pyrazoline benzenesulfonamide derivatives (PBDs) as ERα antagonists using in silico approaches. Structure-based and ligand-based drug design approaches were used to create drug target molecules. A total of forty-five target molecules were initially designed and screened for drug likeness (Lipinski’s rule of five), cytotoxicity, pharmacokinetics and toxicity using a web-based prediction tools. Promising candidates were subjected to molecular docking using AutoDock 4.2.6 to evaluate their binding interaction with ERα, followed by molecular dynamics simulations using AMBER20 to assess complex stability. A pharmacophore model was also generated using LigandScout 4.4.3 Advanced. The molecular docking results identified PBD-17 and PBD-20 as the most promising compounds, with binding free energies (ΔG) of −11.21 kcal/mol and −11.15 kcal/mol, respectively. Both formed hydrogen bonds with key ERα residues ARG394, GLU353, and LEU387. MM-PBSA further supported these findings, with binding energies of −58.23 kJ/mol for PDB-17 and −139.46 kJ/mol for PDB-20, compared to −145.31 kJ/mol, for the reference compound, 4-OHT. Although slightly less favorable than 4-OHT, PBD-20 demonstrated a more stable interaction with ERα than PBD-17. Furthermore, pharmacophore screening showed that both PBD-17 and PBD-20 aligned well with the generated model, each achieving a match score of 45.20. These findings suggest that PBD-17 and PBD-20 are promising lead compounds for the development of a potent ERα inhibitor in breast cancer therapy. |
| format | Article |
| id | doaj-art-5973039aa0374e569fd9537870b8dfd6 |
| institution | DOAJ |
| issn | 2076-3417 |
| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-5973039aa0374e569fd9537870b8dfd62025-08-20T03:02:56ZengMDPI AGApplied Sciences2076-34172025-07-011515844410.3390/app15158444In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα)Dadang Muhammad Hasyim0Ida Musfiroh1Rudi Hendra2Taufik Muhammad Fakih3Nur Kusaira Khairul Ikram4Muchtaridi Muchtaridi5Doctoral Program of Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, West Java, IndonesiaDepartment of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, West Java, IndonesiaDepartment of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Riau, Pekanbaru 28293, Riau, IndonesiaDepartment of Pharmacy, Faculty Mathematics and Natural Sciences, Universitas Islam, Bandung 40116, West Java, IndonesiaInstitute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, MalaysiaDepartment of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, West Java, IndonesiaEstrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modified chalcone compounds into pyrazoline benzenesulfonamide derivatives (Modifina) which show activity as an ERα inhibitor. This study aimed to design novel pyrazoline benzenesulfonamide derivatives (PBDs) as ERα antagonists using in silico approaches. Structure-based and ligand-based drug design approaches were used to create drug target molecules. A total of forty-five target molecules were initially designed and screened for drug likeness (Lipinski’s rule of five), cytotoxicity, pharmacokinetics and toxicity using a web-based prediction tools. Promising candidates were subjected to molecular docking using AutoDock 4.2.6 to evaluate their binding interaction with ERα, followed by molecular dynamics simulations using AMBER20 to assess complex stability. A pharmacophore model was also generated using LigandScout 4.4.3 Advanced. The molecular docking results identified PBD-17 and PBD-20 as the most promising compounds, with binding free energies (ΔG) of −11.21 kcal/mol and −11.15 kcal/mol, respectively. Both formed hydrogen bonds with key ERα residues ARG394, GLU353, and LEU387. MM-PBSA further supported these findings, with binding energies of −58.23 kJ/mol for PDB-17 and −139.46 kJ/mol for PDB-20, compared to −145.31 kJ/mol, for the reference compound, 4-OHT. Although slightly less favorable than 4-OHT, PBD-20 demonstrated a more stable interaction with ERα than PBD-17. Furthermore, pharmacophore screening showed that both PBD-17 and PBD-20 aligned well with the generated model, each achieving a match score of 45.20. These findings suggest that PBD-17 and PBD-20 are promising lead compounds for the development of a potent ERα inhibitor in breast cancer therapy.https://www.mdpi.com/2076-3417/15/15/8444pyrazoline benzenesulfonamideestrogen receptor alphabreast cancer therapydrug designin silico study |
| spellingShingle | Dadang Muhammad Hasyim Ida Musfiroh Rudi Hendra Taufik Muhammad Fakih Nur Kusaira Khairul Ikram Muchtaridi Muchtaridi In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα) Applied Sciences pyrazoline benzenesulfonamide estrogen receptor alpha breast cancer therapy drug design in silico study |
| title | In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα) |
| title_full | In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα) |
| title_fullStr | In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα) |
| title_full_unstemmed | In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα) |
| title_short | In Silico Approaches for the Discovery of Novel Pyrazoline Benzenesulfonamide Derivatives as Anti-Breast Cancer Agents Against Estrogen Receptor Alpha (ERα) |
| title_sort | in silico approaches for the discovery of novel pyrazoline benzenesulfonamide derivatives as anti breast cancer agents against estrogen receptor alpha erα |
| topic | pyrazoline benzenesulfonamide estrogen receptor alpha breast cancer therapy drug design in silico study |
| url | https://www.mdpi.com/2076-3417/15/15/8444 |
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