Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach
We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-dep...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-08-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2019.00574/full |
| _version_ | 1819015773685809152 |
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| author | Hajar Sirous Giulia Chemi Sandra Gemma Stefania Butini Zeger Debyser Frauke Christ Lotfollah Saghaie Simone Brogi Afshin Fassihi Giuseppe Campiani Margherita Brindisi |
| author_facet | Hajar Sirous Giulia Chemi Sandra Gemma Stefania Butini Zeger Debyser Frauke Christ Lotfollah Saghaie Simone Brogi Afshin Fassihi Giuseppe Campiani Margherita Brindisi |
| author_sort | Hajar Sirous |
| collection | DOAJ |
| description | We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN. |
| first_indexed | 2024-12-21T02:37:04Z |
| format | Article |
| id | doaj.art-4d460ecf5e42481b9910ecdcf2d5ff1c |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-21T02:37:04Z |
| publishDate | 2019-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-4d460ecf5e42481b9910ecdcf2d5ff1c2022-12-21T19:18:46ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462019-08-01710.3389/fchem.2019.00574481054Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design ApproachHajar Sirous0Giulia Chemi1Sandra Gemma2Stefania Butini3Zeger Debyser4Frauke Christ5Lotfollah Saghaie6Simone Brogi7Afshin Fassihi8Giuseppe Campiani9Margherita Brindisi10Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, IranDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, ItalyMolecular Medicine, K.U. Leuven and IRC KULAK, Leuven, BelgiumMolecular Medicine, K.U. Leuven and IRC KULAK, Leuven, BelgiumDepartment of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, IranDepartment of Pharmacy, University of Pisa, Pisa, ItalyDepartment of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, IranDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, ItalyDepartment of Pharmacy, Department of Excellence 2018-2022, University of Naples Federico II, Naples, ItalyWe describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN.https://www.frontiersin.org/article/10.3389/fchem.2019.00574/full3-hydroxy-pyran-4-oneHIV-1 integrase inhibitors (HIV-1 INIs)in silico combinatorial library designside chain hoppinghit compounds optimization |
| spellingShingle | Hajar Sirous Giulia Chemi Sandra Gemma Stefania Butini Zeger Debyser Frauke Christ Lotfollah Saghaie Simone Brogi Afshin Fassihi Giuseppe Campiani Margherita Brindisi Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach Frontiers in Chemistry 3-hydroxy-pyran-4-one HIV-1 integrase inhibitors (HIV-1 INIs) in silico combinatorial library design side chain hopping hit compounds optimization |
| title | Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach |
| title_full | Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach |
| title_fullStr | Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach |
| title_full_unstemmed | Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach |
| title_short | Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach |
| title_sort | identification of novel 3 hydroxy pyran 4 one derivatives as potent hiv 1 integrase inhibitors using in silico structure based combinatorial library design approach |
| topic | 3-hydroxy-pyran-4-one HIV-1 integrase inhibitors (HIV-1 INIs) in silico combinatorial library design side chain hopping hit compounds optimization |
| url | https://www.frontiersin.org/article/10.3389/fchem.2019.00574/full |
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