Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA
Given the current epidemic of multidrug-resistant tuberculosis, there is an urgent need to develop new drugs to combat drug-resistant tuberculosis. Direct inhibitors of the InhA target do not require activation and thus can overcome drug resistance caused by mutations in drug-activating enzymes. In...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/17/10102 |
| _version_ | 1797494958125481984 |
|---|---|
| author | Qianqian Zhang Jianting Han Yongchang Zhu Shuoyan Tan Huanxiang Liu |
| author_facet | Qianqian Zhang Jianting Han Yongchang Zhu Shuoyan Tan Huanxiang Liu |
| author_sort | Qianqian Zhang |
| collection | DOAJ |
| description | Given the current epidemic of multidrug-resistant tuberculosis, there is an urgent need to develop new drugs to combat drug-resistant tuberculosis. Direct inhibitors of the InhA target do not require activation and thus can overcome drug resistance caused by mutations in drug-activating enzymes. In this work, the binding thermodynamic and kinetic information of InhA to its direct inhibitors, phenoxyphenol derivatives, were explored through multiple computer-aided drug design (CADD) strategies. The results show that the van der Waals interactions were the main driving force for protein–ligand binding, among which hydrophobic residues such as Tyr158, Phe149, Met199 and Ile202 have high energy contribution. The AHRR pharmacophore model generated by multiple ligands demonstrated that phenoxyphenol derivatives inhibitors can form pi–pi stacking and hydrophobic interactions with InhA target. In addition, the order of residence time predicted by random acceleration molecular dynamics was consistent with the experimental values. The intermediate states of these inhibitors could form hydrogen bonds and van der Waals interactions with surrounding residues during dissociation. Overall, the binding and dissociation mechanisms at the atomic level obtained in this work can provide important theoretical guidance for the development of InhA direct inhibitors with higher activity and proper residence time. |
| first_indexed | 2024-03-10T01:41:42Z |
| format | Article |
| id | doaj.art-c2899b022106430c851437389370f4c5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:41:42Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c2899b022106430c851437389370f4c52023-11-23T13:22:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123171010210.3390/ijms231710102Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhAQianqian Zhang0Jianting Han1Yongchang Zhu2Shuoyan Tan3Huanxiang Liu4Faculty of Applied Science, Macao Polytechnic University, Macao, ChinaCollege of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, ChinaCollege of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, ChinaCollege of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, ChinaFaculty of Applied Science, Macao Polytechnic University, Macao, ChinaGiven the current epidemic of multidrug-resistant tuberculosis, there is an urgent need to develop new drugs to combat drug-resistant tuberculosis. Direct inhibitors of the InhA target do not require activation and thus can overcome drug resistance caused by mutations in drug-activating enzymes. In this work, the binding thermodynamic and kinetic information of InhA to its direct inhibitors, phenoxyphenol derivatives, were explored through multiple computer-aided drug design (CADD) strategies. The results show that the van der Waals interactions were the main driving force for protein–ligand binding, among which hydrophobic residues such as Tyr158, Phe149, Met199 and Ile202 have high energy contribution. The AHRR pharmacophore model generated by multiple ligands demonstrated that phenoxyphenol derivatives inhibitors can form pi–pi stacking and hydrophobic interactions with InhA target. In addition, the order of residence time predicted by random acceleration molecular dynamics was consistent with the experimental values. The intermediate states of these inhibitors could form hydrogen bonds and van der Waals interactions with surrounding residues during dissociation. Overall, the binding and dissociation mechanisms at the atomic level obtained in this work can provide important theoretical guidance for the development of InhA direct inhibitors with higher activity and proper residence time.https://www.mdpi.com/1422-0067/23/17/10102InhA direct inhibitorsphenoxyphenol derivativeshotspot residuespharmacophore modelmolecular dynamics simulationdissociation pathway |
| spellingShingle | Qianqian Zhang Jianting Han Yongchang Zhu Shuoyan Tan Huanxiang Liu Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA International Journal of Molecular Sciences InhA direct inhibitors phenoxyphenol derivatives hotspot residues pharmacophore model molecular dynamics simulation dissociation pathway |
| title | Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA |
| title_full | Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA |
| title_fullStr | Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA |
| title_full_unstemmed | Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA |
| title_short | Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA |
| title_sort | binding thermodynamics and dissociation kinetics analysis uncover the key structural motifs of phenoxyphenol derivatives as the direct inha inhibitors and the hotspot residues of inha |
| topic | InhA direct inhibitors phenoxyphenol derivatives hotspot residues pharmacophore model molecular dynamics simulation dissociation pathway |
| url | https://www.mdpi.com/1422-0067/23/17/10102 |
| work_keys_str_mv | AT qianqianzhang bindingthermodynamicsanddissociationkineticsanalysisuncoverthekeystructuralmotifsofphenoxyphenolderivativesasthedirectinhainhibitorsandthehotspotresiduesofinha AT jiantinghan bindingthermodynamicsanddissociationkineticsanalysisuncoverthekeystructuralmotifsofphenoxyphenolderivativesasthedirectinhainhibitorsandthehotspotresiduesofinha AT yongchangzhu bindingthermodynamicsanddissociationkineticsanalysisuncoverthekeystructuralmotifsofphenoxyphenolderivativesasthedirectinhainhibitorsandthehotspotresiduesofinha AT shuoyantan bindingthermodynamicsanddissociationkineticsanalysisuncoverthekeystructuralmotifsofphenoxyphenolderivativesasthedirectinhainhibitorsandthehotspotresiduesofinha AT huanxiangliu bindingthermodynamicsanddissociationkineticsanalysisuncoverthekeystructuralmotifsofphenoxyphenolderivativesasthedirectinhainhibitorsandthehotspotresiduesofinha |