3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations
Abstract ABT-333 and ABT-072 are two potent non-nucleoside NS5B polymerase inhibitors designed for the treatment of the hepatitis C virus (HCV). These structural analogs differ only by a minor substituent change, which disrupts the planarity of the naphthyl group on the ABT-333 compound through the...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01618-8 |
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| author | Richard S. Hong Alessandra Mattei Mark E. Tuckerman Ahmad Y. Sheikh |
| author_facet | Richard S. Hong Alessandra Mattei Mark E. Tuckerman Ahmad Y. Sheikh |
| author_sort | Richard S. Hong |
| collection | DOAJ |
| description | Abstract ABT-333 and ABT-072 are two potent non-nucleoside NS5B polymerase inhibitors designed for the treatment of the hepatitis C virus (HCV). These structural analogs differ only by a minor substituent change, which disrupts the planarity of the naphthyl group on the ABT-333 compound through the addition of a more flexible trans-olefin substituent. However, this minor change leads to significant differences in their conformational preferences and intermolecular interactions, resulting in a ripple effect with drug development implications, ranging from crystal polymorphism and low aqueous solubility to formulation development challenges. In this article, we demonstrate how a suite of molecular simulation approaches, including crystal structure prediction augmented with a new hydrate CSP algorithm, free-energy perturbation, molecular dynamics (MD) based solubility predictions, and topological assessment to evaluate surface re-crystallization tendencies, provide key atomistic-level insights into the differentiated performance of the two analogs. Through this study, we establish the importance of end-to-end physics-based modeling, which involves explicit considerations of 3-D structure and crystal packing interactions. This approach provides structural and energetic insights into the physicochemical properties and drug development challenges faced when designing best-in-class drug molecules. |
| format | Article |
| id | doaj-art-85f6f2d1ba544dc1b4fe7ab8104834ee |
| institution | Kabale University |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-85f6f2d1ba544dc1b4fe7ab8104834ee2025-08-20T03:42:34ZengNature PortfolioCommunications Chemistry2399-36692025-08-018111110.1038/s42004-025-01618-83D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulationsRichard S. Hong0Alessandra Mattei1Mark E. Tuckerman2Ahmad Y. Sheikh3AbbVie Inc., Molecular Profiling and Drug DeliveryAbbVie Inc., Molecular Profiling and Drug DeliveryDepartment of Chemistry, New York UniversityAbbVie Inc., Molecular Profiling and Drug DeliveryAbstract ABT-333 and ABT-072 are two potent non-nucleoside NS5B polymerase inhibitors designed for the treatment of the hepatitis C virus (HCV). These structural analogs differ only by a minor substituent change, which disrupts the planarity of the naphthyl group on the ABT-333 compound through the addition of a more flexible trans-olefin substituent. However, this minor change leads to significant differences in their conformational preferences and intermolecular interactions, resulting in a ripple effect with drug development implications, ranging from crystal polymorphism and low aqueous solubility to formulation development challenges. In this article, we demonstrate how a suite of molecular simulation approaches, including crystal structure prediction augmented with a new hydrate CSP algorithm, free-energy perturbation, molecular dynamics (MD) based solubility predictions, and topological assessment to evaluate surface re-crystallization tendencies, provide key atomistic-level insights into the differentiated performance of the two analogs. Through this study, we establish the importance of end-to-end physics-based modeling, which involves explicit considerations of 3-D structure and crystal packing interactions. This approach provides structural and energetic insights into the physicochemical properties and drug development challenges faced when designing best-in-class drug molecules.https://doi.org/10.1038/s42004-025-01618-8 |
| spellingShingle | Richard S. Hong Alessandra Mattei Mark E. Tuckerman Ahmad Y. Sheikh 3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations Communications Chemistry |
| title | 3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations |
| title_full | 3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations |
| title_fullStr | 3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations |
| title_full_unstemmed | 3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations |
| title_short | 3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations |
| title_sort | 3d conformation and crystal interaction insights into drug development challenges for hcv drug analogues via molecular simulations |
| url | https://doi.org/10.1038/s42004-025-01618-8 |
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