Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate Synthase
The synthase, 3-deoxy-<span style="font-variant: small-caps;">d</span>-<i>manno</i>-octulosonate 8-phosphate (KDO8P), is a key enzyme for the lipopolysaccharide (LPS) biosynthesis of gram-negative bacteria and a potential target for developing new antimicrobial agen...
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MDPI AG
2019-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/13/2370 |
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| author | Jéssica de Oliveira Araújo Alberto Monteiro dos Santos Jerônimo Lameira Cláudio Nahum Alves Anderson Henrique Lima |
| author_facet | Jéssica de Oliveira Araújo Alberto Monteiro dos Santos Jerônimo Lameira Cláudio Nahum Alves Anderson Henrique Lima |
| author_sort | Jéssica de Oliveira Araújo |
| collection | DOAJ |
| description | The synthase, 3-deoxy-<span style="font-variant: small-caps;">d</span>-<i>manno</i>-octulosonate 8-phosphate (KDO8P), is a key enzyme for the lipopolysaccharide (LPS) biosynthesis of gram-negative bacteria and a potential target for developing new antimicrobial agents. In this study, computational molecular modeling methods were used to determine the complete structure of the KDO8P synthase from <i>Neisseria meningitidis</i> and to investigate the molecular mechanism of its inhibition by three bisphosphate inhibitors: BPH1, BPH2, and BPH3. Our results showed that BPH1 presented a protein−ligand complex with the highest affinity, which is in agreement with experimental data. Furthermore, molecular dynamics (MD) simulations showed that BPH1 is more active due to the many effective interactions, most of which are derived from its phosphoenolpyruvate moiety. Conversely, BPH2 exhibited few hydrogen interactions during the MD simulations with key residues located at the active sites of the KDO8P synthase. In addition, we hydroxylated BPH2 to create the hypothetical molecule named BPH3, to investigate the influence of the hydroxyl groups on the affinity of the bisphosphate inhibitors toward the KDO8P synthase. Overall, we discuss the main interactions between the KDO8P synthase and the bisphosphate inhibitors that are potential starting points for the design of new molecules with significant antibiotic activities. |
| first_indexed | 2024-12-10T11:37:42Z |
| format | Article |
| id | doaj.art-a27d4710324646d79a9a2196aae073a8 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T11:37:42Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a27d4710324646d79a9a2196aae073a82022-12-22T01:50:23ZengMDPI AGMolecules1420-30492019-06-012413237010.3390/molecules24132370molecules24132370Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate SynthaseJéssica de Oliveira Araújo0Alberto Monteiro dos Santos1Jerônimo Lameira2Cláudio Nahum Alves3Anderson Henrique Lima4Laboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Belém 66075-110, BrasilLaboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Belém 66075-110, BrasilLaboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Belém 66075-110, BrasilLaboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Belém 66075-110, BrasilLaboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Belém 66075-110, BrasilThe synthase, 3-deoxy-<span style="font-variant: small-caps;">d</span>-<i>manno</i>-octulosonate 8-phosphate (KDO8P), is a key enzyme for the lipopolysaccharide (LPS) biosynthesis of gram-negative bacteria and a potential target for developing new antimicrobial agents. In this study, computational molecular modeling methods were used to determine the complete structure of the KDO8P synthase from <i>Neisseria meningitidis</i> and to investigate the molecular mechanism of its inhibition by three bisphosphate inhibitors: BPH1, BPH2, and BPH3. Our results showed that BPH1 presented a protein−ligand complex with the highest affinity, which is in agreement with experimental data. Furthermore, molecular dynamics (MD) simulations showed that BPH1 is more active due to the many effective interactions, most of which are derived from its phosphoenolpyruvate moiety. Conversely, BPH2 exhibited few hydrogen interactions during the MD simulations with key residues located at the active sites of the KDO8P synthase. In addition, we hydroxylated BPH2 to create the hypothetical molecule named BPH3, to investigate the influence of the hydroxyl groups on the affinity of the bisphosphate inhibitors toward the KDO8P synthase. Overall, we discuss the main interactions between the KDO8P synthase and the bisphosphate inhibitors that are potential starting points for the design of new molecules with significant antibiotic activities.https://www.mdpi.com/1420-3049/24/13/2370KDO8P synthase<i>Neisseria meningitidis</i>bisphosphate inhibitorsmolecular dynamics |
| spellingShingle | Jéssica de Oliveira Araújo Alberto Monteiro dos Santos Jerônimo Lameira Cláudio Nahum Alves Anderson Henrique Lima Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate Synthase Molecules KDO8P synthase <i>Neisseria meningitidis</i> bisphosphate inhibitors molecular dynamics |
| title | Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate Synthase |
| title_full | Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate Synthase |
| title_fullStr | Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate Synthase |
| title_full_unstemmed | Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate Synthase |
| title_short | Computational Investigation of Bisphosphate Inhibitors of 3-Deoxy-<span style="font-variant: small-caps">d</span>-<i>manno</i>-octulosonate 8-phosphate Synthase |
| title_sort | computational investigation of bisphosphate inhibitors of 3 deoxy span style font variant small caps d span i manno i octulosonate 8 phosphate synthase |
| topic | KDO8P synthase <i>Neisseria meningitidis</i> bisphosphate inhibitors molecular dynamics |
| url | https://www.mdpi.com/1420-3049/24/13/2370 |
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