Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase
In this paper, the Y188C mutant HIV-1 reverse transcriptase (Y188CM-RT) target protein was constructed by homology modeling, and new ligands based on nevirapine (NVP) skeleton were designed by means of fragment growth. The binding activity of new ligands to Y188CM-RT was evaluated by structural anal...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/21/7348 |
| _version_ | 1797467085906903040 |
|---|---|
| author | Yan Wang Aidong Wang Jianhua Wang Xiaoran Wu Yijie Sun Yan Wu |
| author_facet | Yan Wang Aidong Wang Jianhua Wang Xiaoran Wu Yijie Sun Yan Wu |
| author_sort | Yan Wang |
| collection | DOAJ |
| description | In this paper, the Y188C mutant HIV-1 reverse transcriptase (Y188CM-RT) target protein was constructed by homology modeling, and new ligands based on nevirapine (NVP) skeleton were designed by means of fragment growth. The binding activity of new ligands to Y188CM-RT was evaluated by structural analysis, ADMET prediction, molecular docking, energy calculation and molecular dynamics. Results show that 10 new ligands had good absorbability, and their binding energies to Y188CM-RT were significantly higher than those of wild-type HIV-1 reverse transcriptase(wt). The binding mode explained that fragment growth contributed to larger ligands, leading to improved suitability at the docking pocket. In the way of fragment growth, the larger side chain with extensive contact at terminal is obviously better than substituted benzene ring. The enhancement of docking activity is mainly due to the new fragments such as alkyl chains and rings with amino groups at NVP terminal, resulting in a large increase in hydrophobic bonding and the new addition of hydrogen bonding or salt bonding. This study is expected to provide reference for the research on non-nucleoside reverse transcriptase inhibitors resistance and AIDS treatment. |
| first_indexed | 2024-03-09T18:47:41Z |
| format | Article |
| id | doaj.art-1a4cbcdb97db43299385b30f8893791a |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T18:47:41Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1a4cbcdb97db43299385b30f8893791a2023-11-24T06:02:45ZengMDPI AGMolecules1420-30492022-10-012721734810.3390/molecules27217348Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse TranscriptaseYan Wang0Aidong Wang1Jianhua Wang2Xiaoran Wu3Yijie Sun4Yan Wu5Key Laboratory of Drug Design, College of Chemistry and Chemical Engineering, Huangshan University, Huangshan 245061, ChinaKey Laboratory of Drug Design, College of Chemistry and Chemical Engineering, Huangshan University, Huangshan 245061, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing 400044, ChinaKey Laboratory of Drug Design, College of Chemistry and Chemical Engineering, Huangshan University, Huangshan 245061, ChinaKey Laboratory of Drug Design, College of Chemistry and Chemical Engineering, Huangshan University, Huangshan 245061, ChinaKey Laboratory of Drug Design, College of Chemistry and Chemical Engineering, Huangshan University, Huangshan 245061, ChinaIn this paper, the Y188C mutant HIV-1 reverse transcriptase (Y188CM-RT) target protein was constructed by homology modeling, and new ligands based on nevirapine (NVP) skeleton were designed by means of fragment growth. The binding activity of new ligands to Y188CM-RT was evaluated by structural analysis, ADMET prediction, molecular docking, energy calculation and molecular dynamics. Results show that 10 new ligands had good absorbability, and their binding energies to Y188CM-RT were significantly higher than those of wild-type HIV-1 reverse transcriptase(wt). The binding mode explained that fragment growth contributed to larger ligands, leading to improved suitability at the docking pocket. In the way of fragment growth, the larger side chain with extensive contact at terminal is obviously better than substituted benzene ring. The enhancement of docking activity is mainly due to the new fragments such as alkyl chains and rings with amino groups at NVP terminal, resulting in a large increase in hydrophobic bonding and the new addition of hydrogen bonding or salt bonding. This study is expected to provide reference for the research on non-nucleoside reverse transcriptase inhibitors resistance and AIDS treatment.https://www.mdpi.com/1420-3049/27/21/7348nevirapinefragment growthY188C mutation HIV-1 reverse transcriptaseHIV-1molecular docking |
| spellingShingle | Yan Wang Aidong Wang Jianhua Wang Xiaoran Wu Yijie Sun Yan Wu Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase Molecules nevirapine fragment growth Y188C mutation HIV-1 reverse transcriptase HIV-1 molecular docking |
| title | Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase |
| title_full | Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase |
| title_fullStr | Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase |
| title_full_unstemmed | Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase |
| title_short | Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase |
| title_sort | me better drug design based on nevirapine and mechanism of molecular interactions with y188c mutant hiv 1 reverse transcriptase |
| topic | nevirapine fragment growth Y188C mutation HIV-1 reverse transcriptase HIV-1 molecular docking |
| url | https://www.mdpi.com/1420-3049/27/21/7348 |
| work_keys_str_mv | AT yanwang mebetterdrugdesignbasedonnevirapineandmechanismofmolecularinteractionswithy188cmutanthiv1reversetranscriptase AT aidongwang mebetterdrugdesignbasedonnevirapineandmechanismofmolecularinteractionswithy188cmutanthiv1reversetranscriptase AT jianhuawang mebetterdrugdesignbasedonnevirapineandmechanismofmolecularinteractionswithy188cmutanthiv1reversetranscriptase AT xiaoranwu mebetterdrugdesignbasedonnevirapineandmechanismofmolecularinteractionswithy188cmutanthiv1reversetranscriptase AT yijiesun mebetterdrugdesignbasedonnevirapineandmechanismofmolecularinteractionswithy188cmutanthiv1reversetranscriptase AT yanwu mebetterdrugdesignbasedonnevirapineandmechanismofmolecularinteractionswithy188cmutanthiv1reversetranscriptase |