Identification of a new class of FtsZ inhibitors by structure-based design and in vitro screening
| Autor: | Marco A. C. Neves, Yun Chung Leung, Ning Sun, Fung-Yi Chan, Wai Hong Chung, Kwok Yin Wong, Tak Hang Chan, Ruben Abagyan, Dik-Lung Ma, Pak Ho Chan, Polo Chun Hung Lam, Ho Yin Chow, Lai King Wong |
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| Rok vydání: | 2013 |
| Předmět: |
Quinuclidines
Staphylococcus aureus Protein Conformation General Chemical Engineering In silico Mutant Drug Evaluation Preclinical Computational biology Library and Information Sciences Bacterial cell structure Microbiology GTP Phosphohydrolases chemistry.chemical_compound Structure-Activity Relationship Tubulin Escherichia coli Structure–activity relationship Animals Humans Enzyme Inhibitors FtsZ Protein Structure Quaternary Virtual screening Natural product Binding Sites biology Sequence Homology Amino Acid General Chemistry Computer Science Applications Anti-Bacterial Agents Molecular Docking Simulation Pyrimidines chemistry Drug Design biology.protein Cattle Guanosine Triphosphate Protein Multimerization Antibacterial activity |
| Zdroj: | Journal of chemical information and modeling. 53(8) |
| ISSN: | 1549-960X |
| Popis: | The Filamenting temperature-sensitive mutant Z (FtsZ), an essential GTPase in bacterial cell division, is highly conserved among Gram-positive and Gram-negative bacteria and thus considered an attractive target to treat antibiotic-resistant bacterial infections. In this study, a new class of FtsZ inhibitors bearing the pyrimidine-quinuclidine scaffold was identified from structure-based virtual screening of natural product libraries. Iterative rounds of in silico studies and biological evaluation established the preliminary structure–activity relationships of the new compounds. Potent FtsZ inhibitors with low micromolar IC50 and antibacterial activity against S. aureus and E. coli were found. These findings support the use of virtual screening and structure-based design for the rational development of new antibacterial agents with innovative mechanisms of action. |
| Databáze: | OpenAIRE |
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