Article ; Online: In silico docking and molecular dynamics simulation of 3-dehydroquinate synthase (DHQS) from Mycobacterium tuberculosis.
2018 Volume 24, Issue 6, Page(s) 132
Abstract: The shikimate pathway is as an attractive target because it is present in bacteria, algae, fungi, and plants but does not occur in mammals. In Mycobacterium tuberculosis (MTB), the shikimate pathway is integral to the biosynthesis of naphthoquinones, ... ...
| Abstract | The shikimate pathway is as an attractive target because it is present in bacteria, algae, fungi, and plants but does not occur in mammals. In Mycobacterium tuberculosis (MTB), the shikimate pathway is integral to the biosynthesis of naphthoquinones, menaquinones, and mycobactin. In these study, novel inhibitors of 3-dehydroquinate synthase (DHQS), an enzyme that catalyzes the second step of the shikimate pathway in MTB, were determined. 12,165 compounds were selected from two public databases through virtual screening and molecular docking analysis using PyRx 8.0 and Autodock 4.2, respectively. A total of 18 compounds with the best binding energies (-13.23 to -8.22 kcal/mol) were then selected and screened for absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, and nine of those compounds were found to satisfy all of the ADME and toxicity criteria. Among those nine, the three compounds-ZINC633887 (binding energy = -10.29 kcal/mol), ZINC08983432 (-9.34 kcal/mol), and PubChem73393 (-8.61 kcal/mol)-with the best binding energies were further selected for molecular dynamics (MD) simulation analysis. The results of the 50-ns MD simulations showed that the two compounds ZINC633887 and PubChem73393 formed stable complexes with DHQS and that the structures of those two ligands remained largely unchanged at the ligand-binding site during the simulations. These two compounds identified through docking and MD simulation are potential candidates for the treatment of TB, and should undergo validation in vivo and in vitro. |
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| MeSH term(s) | Bacterial Proteins/chemistry ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mycobacterium tuberculosis/enzymology ; Phosphorus-Oxygen Lyases/chemistry |
| Chemical Substances | Bacterial Proteins ; 3-dehydroquinate synthetase (EC 4.2.3.4) ; Phosphorus-Oxygen Lyases (EC 4.6.-) |
| Language | English |
| Publishing date | 2018-05-11 |
| Publishing country | Germany |
| Document type | Journal Article |
| ZDB-ID | 1284729-x |
| ISSN | 0948-5023 ; 1610-2940 |
| ISSN (online) | 0948-5023 |
| ISSN | 1610-2940 |
| DOI | 10.1007/s00894-018-3637-4 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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