Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease
Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability...
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| Format: | Article |
| Language: | English |
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MDPI AG
2012-05-01
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| Series: | Biology |
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| Online Access: | http://www.mdpi.com/2079-7737/1/1/81 |
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| author | Ladislau C. Kovari Iulia A. Kovari Joseph S. Brunzelle Samuel J. Reiter Zhigang Liu Tamaria G. Dewdney Yong Wang |
| author_facet | Ladislau C. Kovari Iulia A. Kovari Joseph S. Brunzelle Samuel J. Reiter Zhigang Liu Tamaria G. Dewdney Yong Wang |
| author_sort | Ladislau C. Kovari |
| collection | DOAJ |
| description | Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates. |
| first_indexed | 2024-03-12T09:53:58Z |
| format | Article |
| id | doaj.art-055133f440844825ada986e86738ae08 |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-12T09:53:58Z |
| publishDate | 2012-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-055133f440844825ada986e86738ae082023-09-02T12:16:50ZengMDPI AGBiology2079-77372012-05-0111819310.3390/biology1010081Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 ProteaseLadislau C. KovariIulia A. KovariJoseph S. BrunzelleSamuel J. ReiterZhigang LiuTamaria G. DewdneyYong WangDesigning HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.http://www.mdpi.com/2079-7737/1/1/81multi-drug resistant HIV-1 proteaseX-ray crystallographydesolvation energy |
| spellingShingle | Ladislau C. Kovari Iulia A. Kovari Joseph S. Brunzelle Samuel J. Reiter Zhigang Liu Tamaria G. Dewdney Yong Wang Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease Biology multi-drug resistant HIV-1 protease X-ray crystallography desolvation energy |
| title | Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease |
| title_full | Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease |
| title_fullStr | Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease |
| title_full_unstemmed | Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease |
| title_short | Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease |
| title_sort | higher desolvation energy reduces molecular recognition in multi drug resistant hiv 1 protease |
| topic | multi-drug resistant HIV-1 protease X-ray crystallography desolvation energy |
| url | http://www.mdpi.com/2079-7737/1/1/81 |
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