Trehalose synthesis inhibitor: A molecular in silico drug design
| Autor: | Lucas Machado Gonçalves, Eduardo T. V. Trevisol, Joelma Freire De Mesquita, Bárbara de Azevedo Abrahim Vieira |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular 0301 basic medicine Saccharomyces cerevisiae Proteins Molecular model Protein Conformation In silico Population Saccharomyces cerevisiae Computational biology Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Computer Simulation Enzyme Inhibitors education Molecular Biology education.field_of_study biology Chemistry Trehalose Cell Biology Ligand (biochemistry) biology.organism_classification Molecular Docking Simulation 030104 developmental biology Drug development Glucosyltransferases Drug Design 030220 oncology & carcinogenesis Sugar Phosphates Uncompetitive inhibitor |
| Zdroj: | Journal of Cellular Biochemistry. 121:1114-1125 |
| ISSN: | 1097-4644 0730-2312 |
| DOI: | 10.1002/jcb.29347 |
| Popis: | Infectious diseases are serious public health problems, affecting a large portion of the world's population. A molecule that plays a key role in pathogenic organisms is trehalose and recently has been an interest in the metabolism of this molecule for drug development. The trehalose-6-phosphate synthase (TPS1) is an enzyme responsible for the biosynthesis of trehalose-6-phosphate (T6P) in the TPS1/TPS2 pathway, which results in the formation of trehalose. Studies carried out by our group demonstrated the inhibitory capacity of T6P in the TPS1 enzyme from Saccharomyces cerevisiae, preventing the synthesis of trehalose. By in silico techniques, we compiled sequences and experimentally determined structures of TPS1. Sequence alignments and molecular modeling were performed. The generated structures were submitted in validation of algorithms, aligned structurally and analyzed evolutionarily. Molecular docking methodology was applied to analyze the interaction between T6P and TPS1 and ADMET properties of T6P were analyzed. The results demonstrated the models created presented sequence and structural similarities with experimentally determined structures. With the molecular docking, a cavity in the protein surface was identified and the molecule T6P was interacting with the residues TYR-40, ALA-41, MET-42, and PHE-372, indicating the possible uncompetitive inhibition mechanism provided by this ligand, which can be useful in directing the molecular design of inhibitors. In ADMET analyses, T6P had acceptable risk values compared with other compounds from World Drug Index. Therefore, these results may present a promising strategy to explore to develop a broad-spectrum antibiotic of this specific target with selectivity, potency, and reduced side effects, leading to a new way to treat infectious diseases like tuberculosis and candidiasis. |
| Databáze: | OpenAIRE |
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