Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studies
Fungal infections are a growing public health problem worldwide. Despite the availability of several medicines, their efficacy is still constrained by fungal resistance. This research conducted the 2D/3D-QSAR analysis on twenty-nine triazole molecules previously evaluated for their antifungal activi...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Chemical Physics Impact |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S266702242400046X |
| _version_ | 1827221626125549568 |
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| author | Soukaina Bouamrane Ayoub Khaldan Marwa Alaqarbeh Abdelouahid Sbai Mohammed Aziz Ajana Tahar Lakhlifi Mohammed Bouachrine Hamid Maghat |
| author_facet | Soukaina Bouamrane Ayoub Khaldan Marwa Alaqarbeh Abdelouahid Sbai Mohammed Aziz Ajana Tahar Lakhlifi Mohammed Bouachrine Hamid Maghat |
| author_sort | Soukaina Bouamrane |
| collection | DOAJ |
| description | Fungal infections are a growing public health problem worldwide. Despite the availability of several medicines, their efficacy is still constrained by fungal resistance. This research conducted the 2D/3D-QSAR analysis on twenty-nine triazole molecules previously evaluated for their antifungal activity. The HQSAR/B-H, CoMFA and CoMSIA models were built using twenty-three molecules in the training set. They show high Q2 values (0.646, 0.564 and 0.561, respectively) and important R2 values (0.764, 0.805 and 0.787, respectively). The predictive capacity of the established models was validated by external validation; they performed well. The contour maps derived from the HQSAR/B-H, CoMFA and CoMSIA models provide more detail to identify favorable and unfavorable groupings impacting the activity. Then, 4 proposed new triazole molecules with significant antifungal activity were suggested. In addition, the molecular docking results showed good binding energies and interactions of the proposed inhibitors in the active site of the receptor studied. The molecular dynamics and MM/PBSA methods confirmed and validated the molecular docking results. The new triazole molecules were evaluated for their oral bioavailability and toxicity using ADME/Tox properties. Finally, the retrosynthesis method created a synthetic pathway for the candidate inhibitor Z1. |
| first_indexed | 2024-03-07T20:04:35Z |
| format | Article |
| id | doaj.art-ed52f1aba3dd48468596591a87199319 |
| institution | Directory Open Access Journal |
| issn | 2667-0224 |
| language | English |
| last_indexed | 2025-03-21T16:25:35Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Chemical Physics Impact |
| spelling | doaj.art-ed52f1aba3dd48468596591a871993192024-06-17T05:59:46ZengElsevierChemical Physics Impact2667-02242024-06-018100502Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studiesSoukaina Bouamrane0Ayoub Khaldan1Marwa Alaqarbeh2Abdelouahid Sbai3Mohammed Aziz Ajana4Tahar Lakhlifi5Mohammed Bouachrine6Hamid Maghat7Molecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University of Meknes, MoroccoMolecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University of Meknes, MoroccoBasic Science Department, Prince Al Hussein bin Abdullah II Academy for Civil Protection, Al-Balqa Applied University, Al-Salt 19117, Jordan; Corresponding author.Molecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University of Meknes, MoroccoMolecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University of Meknes, MoroccoMolecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University of Meknes, MoroccoMolecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University of Meknes, MoroccoMolecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University of Meknes, MoroccoFungal infections are a growing public health problem worldwide. Despite the availability of several medicines, their efficacy is still constrained by fungal resistance. This research conducted the 2D/3D-QSAR analysis on twenty-nine triazole molecules previously evaluated for their antifungal activity. The HQSAR/B-H, CoMFA and CoMSIA models were built using twenty-three molecules in the training set. They show high Q2 values (0.646, 0.564 and 0.561, respectively) and important R2 values (0.764, 0.805 and 0.787, respectively). The predictive capacity of the established models was validated by external validation; they performed well. The contour maps derived from the HQSAR/B-H, CoMFA and CoMSIA models provide more detail to identify favorable and unfavorable groupings impacting the activity. Then, 4 proposed new triazole molecules with significant antifungal activity were suggested. In addition, the molecular docking results showed good binding energies and interactions of the proposed inhibitors in the active site of the receptor studied. The molecular dynamics and MM/PBSA methods confirmed and validated the molecular docking results. The new triazole molecules were evaluated for their oral bioavailability and toxicity using ADME/Tox properties. Finally, the retrosynthesis method created a synthetic pathway for the candidate inhibitor Z1.http://www.sciencedirect.com/science/article/pii/S266702242400046XCoMFACoMSIAHQSARLipinski's ruleProtein–ligand interaction |
| spellingShingle | Soukaina Bouamrane Ayoub Khaldan Marwa Alaqarbeh Abdelouahid Sbai Mohammed Aziz Ajana Tahar Lakhlifi Mohammed Bouachrine Hamid Maghat Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studies Chemical Physics Impact CoMFA CoMSIA HQSAR Lipinski's rule Protein–ligand interaction |
| title | Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studies |
| title_full | Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studies |
| title_fullStr | Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studies |
| title_full_unstemmed | Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studies |
| title_short | Computational integration for antifungal 1,2,4-triazole inhibitors design: QSAR, molecular docking, molecular dynamics simulations, ADME/Tox, and retrosynthesis studies |
| title_sort | computational integration for antifungal 1 2 4 triazole inhibitors design qsar molecular docking molecular dynamics simulations adme tox and retrosynthesis studies |
| topic | CoMFA CoMSIA HQSAR Lipinski's rule Protein–ligand interaction |
| url | http://www.sciencedirect.com/science/article/pii/S266702242400046X |
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