Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1
Cancer remains a major global health concern due to chemotherapy resistance and toxicity from high-dose treatments. To overcome these challenges, new therapeutic strategies targeting key proteins in cancer progression are essential. This study evaluates two phytochemicals, Carpaine (Car) and Rutin (...
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Elsevier
2025-08-01
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| Series: | Phytomedicine Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667031325001010 |
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| author | Merla Sudha Asmita Saha Belaguppa Manjunath Ashwin Desai Anil Ranu Mhashal Pronama Biswas |
| author_facet | Merla Sudha Asmita Saha Belaguppa Manjunath Ashwin Desai Anil Ranu Mhashal Pronama Biswas |
| author_sort | Merla Sudha |
| collection | DOAJ |
| description | Cancer remains a major global health concern due to chemotherapy resistance and toxicity from high-dose treatments. To overcome these challenges, new therapeutic strategies targeting key proteins in cancer progression are essential. This study evaluates two phytochemicals, Carpaine (Car) and Rutin (Rut), from Carica papaya leaves, for their potential in enhancing cancer therapy by targeting B-cell lymphoma 2 (BCL-2) and WW domain-containing protein 1 (WWP1) proteins. We assessed their additive, allosteric, and synergistic effects using molecular docking, multi-ligand simultaneous docking (MLSD), molecular dynamics (MD) simulations, and MMPBSA analysis. Car and Rut showed an additive effect on BCL-2 by binding at distinct regions within the same pocket. MLSD revealed an improved binding affinity of -13.13 ± 0.08 kcal/mol, individual ligands or the commercial inhibitor Venetoclax. For WWP1, Car bound near the H-site and Rut near the Le-site, exhibiting an allosteric effect that increased Car’s binding affinity in MLSD to -15.59 ± 0.39 kcal/mol. Furthermore, Rut combined with bortezomib (Bortezomib) demonstrated a synergistic interaction with WWP1. Binding energies were -7.64 ± 0.156 kcal/mol for Bort, -10.26 ± 0.07 kcal/mol for Rut, and -15.59 ± 0.39 kcal/mol for MLSD, suggesting a more stable complex through synergy. These results suggest Car and Rut, particularly in combination with Bort, as promising candidates against cancer-related proteins BCL-2 and WWP1. Further experimental validation is warranted to explore their therapeutic potential. |
| format | Article |
| id | doaj-art-df188645cf3c4bd88fdeb6d9918ea07d |
| institution | Kabale University |
| issn | 2667-0313 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Phytomedicine Plus |
| spelling | doaj-art-df188645cf3c4bd88fdeb6d9918ea07d2025-08-21T04:17:30ZengElsevierPhytomedicine Plus2667-03132025-08-015310082910.1016/j.phyplu.2025.100829Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1Merla Sudha0Asmita Saha1Belaguppa Manjunath Ashwin Desai2Anil Ranu Mhashal3Pronama Biswas4Department of Biological Sciences, School of Basic and Applied Sciences, Dayananda Sagar University, Bengaluru, IndiaDepartment of Biological Sciences, School of Basic and Applied Sciences, Dayananda Sagar University, Bengaluru, IndiaSchool of Engineering, Dayananda Sagar University, Bengaluru, IndiaPrescience Insilico Private Limited, Bangaluru, IndiaDepartment of Biological Sciences, School of Basic and Applied Sciences, Dayananda Sagar University, Bengaluru, India; Corresponding author.Cancer remains a major global health concern due to chemotherapy resistance and toxicity from high-dose treatments. To overcome these challenges, new therapeutic strategies targeting key proteins in cancer progression are essential. This study evaluates two phytochemicals, Carpaine (Car) and Rutin (Rut), from Carica papaya leaves, for their potential in enhancing cancer therapy by targeting B-cell lymphoma 2 (BCL-2) and WW domain-containing protein 1 (WWP1) proteins. We assessed their additive, allosteric, and synergistic effects using molecular docking, multi-ligand simultaneous docking (MLSD), molecular dynamics (MD) simulations, and MMPBSA analysis. Car and Rut showed an additive effect on BCL-2 by binding at distinct regions within the same pocket. MLSD revealed an improved binding affinity of -13.13 ± 0.08 kcal/mol, individual ligands or the commercial inhibitor Venetoclax. For WWP1, Car bound near the H-site and Rut near the Le-site, exhibiting an allosteric effect that increased Car’s binding affinity in MLSD to -15.59 ± 0.39 kcal/mol. Furthermore, Rut combined with bortezomib (Bortezomib) demonstrated a synergistic interaction with WWP1. Binding energies were -7.64 ± 0.156 kcal/mol for Bort, -10.26 ± 0.07 kcal/mol for Rut, and -15.59 ± 0.39 kcal/mol for MLSD, suggesting a more stable complex through synergy. These results suggest Car and Rut, particularly in combination with Bort, as promising candidates against cancer-related proteins BCL-2 and WWP1. Further experimental validation is warranted to explore their therapeutic potential.http://www.sciencedirect.com/science/article/pii/S2667031325001010Additive effectAllosterismB-cell lymphoma 2Carica papayaCombinational therapyMulti-ligand simultaneous docking |
| spellingShingle | Merla Sudha Asmita Saha Belaguppa Manjunath Ashwin Desai Anil Ranu Mhashal Pronama Biswas Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1 Phytomedicine Plus Additive effect Allosterism B-cell lymphoma 2 Carica papaya Combinational therapy Multi-ligand simultaneous docking |
| title | Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1 |
| title_full | Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1 |
| title_fullStr | Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1 |
| title_full_unstemmed | Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1 |
| title_short | Multi-ligand simultaneous docking of Carica papaya leaf phytochemicals, Carpaine and Rutin reveal multi-mechanism inhibition of cancer proteins, BCL-2 and WWP1 |
| title_sort | multi ligand simultaneous docking of carica papaya leaf phytochemicals carpaine and rutin reveal multi mechanism inhibition of cancer proteins bcl 2 and wwp1 |
| topic | Additive effect Allosterism B-cell lymphoma 2 Carica papaya Combinational therapy Multi-ligand simultaneous docking |
| url | http://www.sciencedirect.com/science/article/pii/S2667031325001010 |
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