Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents
Plasmodium falciparum dihydrofolate reductase (PfDHFR) is a promising therapeutic target for antimalarial interventions. Diaminodihydrotriazine derivatives have demonstrated their efficacy as antimalarial agents by targeting PfDHFR inhibition. In this study, we used a multifaceted approach including...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Scientific African |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468227624001480 |
| _version_ | 1797220283912814592 |
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| author | Nedjla Khelfa Salah Belaidi Oussama Abchir Imane Yamari Samir Chtita Abdelouahid Samadi Muneerah Mogren Al-Mogren Majdi Hochlaf |
| author_facet | Nedjla Khelfa Salah Belaidi Oussama Abchir Imane Yamari Samir Chtita Abdelouahid Samadi Muneerah Mogren Al-Mogren Majdi Hochlaf |
| author_sort | Nedjla Khelfa |
| collection | DOAJ |
| description | Plasmodium falciparum dihydrofolate reductase (PfDHFR) is a promising therapeutic target for antimalarial interventions. Diaminodihydrotriazine derivatives have demonstrated their efficacy as antimalarial agents by targeting PfDHFR inhibition. In this study, we used a multifaceted approach including 3D-QSAR, in silico pharmacokinetic/ADMET evaluation, molecular docking techniques, and molecular dynamics simulation to explore a series of diaminodihydrotriazine compounds, to identify new antimalarial drug candidates featuring the diaminodihydrotriazine scaffold. Using comparative molecular similarity indices analysis (CoMSIA), we built a robust 3D-QSAR model exhibiting favorable statistical parameters, with Q2 and R2 values of 0.553 and 0.981, respectively. External validation using a test set yielded an R2pre value of 0.787, confirming the model's predictive ability. In addition, we performed comprehensive ADMET and drug similarity profile analyses for potent designed compounds, yielding promising results. Molecular docking studies further complemented our investigation facilitating the elucidation of optimal interaction modes between these inhibitors and their target receptor. Additionally, molecular dynamics simulation was conducted for the promising compound 8a. This study not only provides valuable insights into the design of new antimalarial agents but also highlights the importance of computational methods for accelerating drug discovery processes, particularly in the context of infectious disease control. |
| first_indexed | 2024-04-24T12:47:05Z |
| format | Article |
| id | doaj.art-ab45d1614d5e4ab2a876b2e531f99ecc |
| institution | Directory Open Access Journal |
| issn | 2468-2276 |
| language | English |
| last_indexed | 2024-04-24T12:47:05Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Scientific African |
| spelling | doaj.art-ab45d1614d5e4ab2a876b2e531f99ecc2024-04-07T04:36:03ZengElsevierScientific African2468-22762024-06-0124e02202Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agentsNedjla Khelfa0Salah Belaidi1Oussama Abchir2Imane Yamari3Samir Chtita4Abdelouahid Samadi5Muneerah Mogren Al-Mogren6Majdi Hochlaf7University of Biskra, Group of Computational and Medicinal Chemistry, LMCE Laboratory, BP 145 Biskra 07000, AlgeriaUniversity of Biskra, Group of Computational and Medicinal Chemistry, LMCE Laboratory, BP 145 Biskra 07000, Algeria; Corresponding authors.Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Sidi Othman, Box 7955, Casablanca, MoroccoLaboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Sidi Othman, Box 7955, Casablanca, MoroccoLaboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Sidi Othman, Box 7955, Casablanca, Morocco; Corresponding authors.Department of Chemistry, College of Science, UAEU, P.O. Box No. 15551, Al Ain, UAE; Corresponding authors.Department of Chemistry, College of Sciences, King Saud University, PO Box 2455, Riyadh 11451, Saudi ArabiaUniversité Gustave Eiffel, COSYS/IMSE, 5 Bd Descartes, 77454, Champs sur Marne, FrancePlasmodium falciparum dihydrofolate reductase (PfDHFR) is a promising therapeutic target for antimalarial interventions. Diaminodihydrotriazine derivatives have demonstrated their efficacy as antimalarial agents by targeting PfDHFR inhibition. In this study, we used a multifaceted approach including 3D-QSAR, in silico pharmacokinetic/ADMET evaluation, molecular docking techniques, and molecular dynamics simulation to explore a series of diaminodihydrotriazine compounds, to identify new antimalarial drug candidates featuring the diaminodihydrotriazine scaffold. Using comparative molecular similarity indices analysis (CoMSIA), we built a robust 3D-QSAR model exhibiting favorable statistical parameters, with Q2 and R2 values of 0.553 and 0.981, respectively. External validation using a test set yielded an R2pre value of 0.787, confirming the model's predictive ability. In addition, we performed comprehensive ADMET and drug similarity profile analyses for potent designed compounds, yielding promising results. Molecular docking studies further complemented our investigation facilitating the elucidation of optimal interaction modes between these inhibitors and their target receptor. Additionally, molecular dynamics simulation was conducted for the promising compound 8a. This study not only provides valuable insights into the design of new antimalarial agents but also highlights the importance of computational methods for accelerating drug discovery processes, particularly in the context of infectious disease control.http://www.sciencedirect.com/science/article/pii/S2468227624001480DiaminodihydrotriazinePfDHFR3D-QSARADMETMolecular docking |
| spellingShingle | Nedjla Khelfa Salah Belaidi Oussama Abchir Imane Yamari Samir Chtita Abdelouahid Samadi Muneerah Mogren Al-Mogren Majdi Hochlaf Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents Scientific African Diaminodihydrotriazine PfDHFR 3D-QSAR ADMET Molecular docking |
| title | Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents |
| title_full | Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents |
| title_fullStr | Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents |
| title_full_unstemmed | Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents |
| title_short | Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents |
| title_sort | combined 3d qsar molecular docking admet and drug likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents |
| topic | Diaminodihydrotriazine PfDHFR 3D-QSAR ADMET Molecular docking |
| url | http://www.sciencedirect.com/science/article/pii/S2468227624001480 |
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