Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies
Abstract Cyclotriazadisulfonamide (CADA) is a macrocyclic compound known for its unique mechanism in inhibiting HIV infection by downregulating the CD4 T-cell receptor, a crucial entry point for the virus. Unlike other antiretrovirals, CADA exhibits activity against a wide range of HIV strains, as a...
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Nature Portfolio
2024-11-01
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| Online Access: | https://doi.org/10.1038/s41598-024-77106-1 |
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| author | Jay Gabriel B. Larga Wrynan T. Munabirul Abu Tayab Moin Md Maisum Sarwar Jyoti Mst Sanjida Nasrin Minhaz Abdullah Al Mueid Abdul Ahad Anwar Parvez Mst Sabrina Yeasmin Rupali M. Barhate Rajesh B. Patil Margel C. Bonifacio |
| author_facet | Jay Gabriel B. Larga Wrynan T. Munabirul Abu Tayab Moin Md Maisum Sarwar Jyoti Mst Sanjida Nasrin Minhaz Abdullah Al Mueid Abdul Ahad Anwar Parvez Mst Sabrina Yeasmin Rupali M. Barhate Rajesh B. Patil Margel C. Bonifacio |
| author_sort | Jay Gabriel B. Larga |
| collection | DOAJ |
| description | Abstract Cyclotriazadisulfonamide (CADA) is a macrocyclic compound known for its unique mechanism in inhibiting HIV infection by downregulating the CD4 T-cell receptor, a crucial entry point for the virus. Unlike other antiretrovirals, CADA exhibits activity against a wide range of HIV strains, as all HIV variants require CD4 binding for infection. Furthermore, CADA has shown a synergistic effect with clinically approved anti-HIV drugs, offering potential for enhanced therapeutic strategies (Vermeire & Schols, [65]). One proposed mechanism for CADA’s inhibition of the CD4 receptor involves blocking the gates of the Sec61 channel, thereby preventing its translocation. However, CADA suffers from poor solubility and bioavailability. To address this, the study aimed to design CADA analogs with improved binding to the Sec61 channel, enhanced bioavailability, and reduced toxicity. The analogs were designed using SeeSAR, with Avogadro and Meeko used for 3D configuration and pseudoatom placement, respectively. AutoDock Vina version 1.2.4 was employed to predict the binding energies of these analogs. Of the 113 analogs designed, 93 demonstrated a more negative binding energy to the Sec61 channel compared to CADA. Structure-binding energy analyses were done to the top-binding analogs to show favorable structural modifications. Enzyme-ligand interactions were analyzed to elucidate the forces contributing to these binding energies. Additionally, 33 of the 113 analogs were deemed bioavailable using a bioavailability criteria specific for macrocycles. Toxicity predictions using PASS Online and StopTox identified analogs JGL023, JGL024, JGL032, and JGL047 as potential drug candidates. Molecular dynamics simulations using Gromacs-2020.4 revealed that JGL023 and JGL032 exhibited the most favorable binding to the Sec61 channel, as determined by evaluating ligand and residue flexibility, compactness, contact frequency, motion pathways, free energy, and other relevant parameters. Synthetic routes for these four analogs were proposed for future studies. The results of this study offer a new perspective on developing drugs to inhibit HIV entry. |
| format | Article |
| id | doaj-art-bc18614db3ec4c3ea2c62ee77a7e9d4c |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-bc18614db3ec4c3ea2c62ee77a7e9d4c2025-02-02T12:25:21ZengNature PortfolioScientific Reports2045-23222024-11-0114112910.1038/s41598-024-77106-1Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapiesJay Gabriel B. Larga0Wrynan T. Munabirul1Abu Tayab Moin2Md Maisum Sarwar Jyoti3Mst Sanjida Nasrin4Minhaz Abdullah Al Mueid5Abdul Ahad6Anwar Parvez7Mst Sabrina Yeasmin8Rupali M. Barhate9Rajesh B. Patil10Margel C. Bonifacio11Department of Biochemistry, College of Allied Sciences, De La Salle Medical and Health Sciences Institute, City of DasmariñasDepartment of Biochemistry, College of Allied Sciences, De La Salle Medical and Health Sciences Institute, City of DasmariñasDepartment of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of ChittagongDepartment of Bioscience, Graduate School of Science and Technology, National University Corporation Shizuoka UniversityDepartment of Bioinformatics, School of Biosciences, University of SkövdeDepartment of Pharmacy, Faculty of Biological Science, Jahangirnagar UniversityDepartment of Pharmacy, Jagannath UniversityDepartment of Pharmacy, Faculty of Health and Life Sciences, Daffodil International UniversityDepartment of Pharmacy, Independent University BangladeshDepartment of Pharmaceutical Chemistry, Sinhgad Technical Education Society’s, Sinhgad College of PharmacyDepartment of Pharmaceutical Chemistry, Sinhgad Technical Education Society’s, Sinhgad College of PharmacyDepartment of Biochemistry, College of Allied Sciences, De La Salle Medical and Health Sciences Institute, City of DasmariñasAbstract Cyclotriazadisulfonamide (CADA) is a macrocyclic compound known for its unique mechanism in inhibiting HIV infection by downregulating the CD4 T-cell receptor, a crucial entry point for the virus. Unlike other antiretrovirals, CADA exhibits activity against a wide range of HIV strains, as all HIV variants require CD4 binding for infection. Furthermore, CADA has shown a synergistic effect with clinically approved anti-HIV drugs, offering potential for enhanced therapeutic strategies (Vermeire & Schols, [65]). One proposed mechanism for CADA’s inhibition of the CD4 receptor involves blocking the gates of the Sec61 channel, thereby preventing its translocation. However, CADA suffers from poor solubility and bioavailability. To address this, the study aimed to design CADA analogs with improved binding to the Sec61 channel, enhanced bioavailability, and reduced toxicity. The analogs were designed using SeeSAR, with Avogadro and Meeko used for 3D configuration and pseudoatom placement, respectively. AutoDock Vina version 1.2.4 was employed to predict the binding energies of these analogs. Of the 113 analogs designed, 93 demonstrated a more negative binding energy to the Sec61 channel compared to CADA. Structure-binding energy analyses were done to the top-binding analogs to show favorable structural modifications. Enzyme-ligand interactions were analyzed to elucidate the forces contributing to these binding energies. Additionally, 33 of the 113 analogs were deemed bioavailable using a bioavailability criteria specific for macrocycles. Toxicity predictions using PASS Online and StopTox identified analogs JGL023, JGL024, JGL032, and JGL047 as potential drug candidates. Molecular dynamics simulations using Gromacs-2020.4 revealed that JGL023 and JGL032 exhibited the most favorable binding to the Sec61 channel, as determined by evaluating ligand and residue flexibility, compactness, contact frequency, motion pathways, free energy, and other relevant parameters. Synthetic routes for these four analogs were proposed for future studies. The results of this study offer a new perspective on developing drugs to inhibit HIV entry.https://doi.org/10.1038/s41598-024-77106-1Cyclotriazadisulfonamide (CADA)Sec61 channelCD4 T-cell receptorMolecular dockingMolecular dynamics simulation |
| spellingShingle | Jay Gabriel B. Larga Wrynan T. Munabirul Abu Tayab Moin Md Maisum Sarwar Jyoti Mst Sanjida Nasrin Minhaz Abdullah Al Mueid Abdul Ahad Anwar Parvez Mst Sabrina Yeasmin Rupali M. Barhate Rajesh B. Patil Margel C. Bonifacio Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies Scientific Reports Cyclotriazadisulfonamide (CADA) Sec61 channel CD4 T-cell receptor Molecular docking Molecular dynamics simulation |
| title | Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies |
| title_full | Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies |
| title_fullStr | Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies |
| title_full_unstemmed | Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies |
| title_short | Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies |
| title_sort | cutting edge bioinformatics strategies for synthesizing cyclotriazadisulfonamide cada analogs in next generation hiv therapies |
| topic | Cyclotriazadisulfonamide (CADA) Sec61 channel CD4 T-cell receptor Molecular docking Molecular dynamics simulation |
| url | https://doi.org/10.1038/s41598-024-77106-1 |
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