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Multi-target Parallel Processing Approach for Gene-to-structure Determination of the Influenza Polymerase PB2 Subunit
Published on: June 28, 2013
Computational Modelling, Functional Characterization and Molecular Docking to Lead Compounds of Bordetella pertussis
Shilpy Singh1, Afsana Praveen1, Suruchi M Khanna2
1Department of Biotechnology and Microbiology, School of Sciences, Noida International University, Gautam Budh Nagar, U.P, 203201, India.
Abstract:
Bordetella pertussis, the causative agent of whooping cough, is an opportunistic virulent bacterial pathogen that is resistant to a wide range of antibiotics due to a variety of resistance mechanisms. Looking at the increasing number of infections caused by B. pertussis and its resistance to diverse antibiotics, it is essential to develop alternative strategies to fight against B. pertussis. Diaminopimelate epimerase (DapF) is an important enzyme of the lysine biosynthesis pathway in B. pertussis that catalyzes the formation of meso-2, 6-diaminoheptanedioate (meso-DAP), which is an important step in lysine metabolism. Therefore, Bordetella pertussis diaminopimelate epimerase (DapF) becomes an ideal target for antimicrobial drug development. In the present study, computational modelling, functional characterization, binding studies, and docking studies of BpDapF with lead compounds were carried out using different in silico tools. In silico prediction results in the secondary structure, 3-D structure analysis, and protein-protein interaction analysis of BpDapF. Docking studies further showed the respective amino acid residues for ligands in the phosphate‑binding loop of BpDapF play a vital role in the formation of H‑bonds with these ligands. The site where the ligand was bound is a deep groove, which is regarded as the binding cavity of the protein. Biochemical studies indicated that Limonin (binding energy - 8.8 kcal/mol), Ajmalicine (binding energy - 8.7 kcal/mol), Clinafloxacin (binding energy - 8.3 kcal/mol), Dexamethasone (binding energy - 8.2 kcal/mol), and Tetracycline (binding energy - 8.1 kcal/mol) exhibited promising binding towards the drug target DapF of B. pertussis in comparison with the binding between other drugs and act as the potential inhibitors of BpDapF that eventually can reduce the catalytic activity of BpDapF.
Insights
Antibiotic-resistant Bordetella pertussis poses a threat, necessitating new treatments. Researchers identified Bordetella pertussis diaminopimelate epimerase (DapF) as a drug target, with compounds like Limonin showing potential inhibition.
Area of Science:
- Microbiology
- Biochemistry
- Computational Biology
Background:
- Bordetella pertussis causes whooping cough and exhibits antibiotic resistance.
- Novel therapeutic strategies are needed to combat increasing B. pertussis infections.
- Diaminopimelate epimerase (DapF) is crucial for lysine biosynthesis in B. pertussis and represents a potential drug target.
Purpose of the Study:
- To identify potential inhibitors of Bordetella pertussis diaminopimelate epimerase (BpDapF).
- To computationally model and characterize BpDapF and its interactions with lead compounds.
- To evaluate the binding affinity of various compounds to BpDapF for antimicrobial drug development.
Main Methods:
- In silico computational modeling, including secondary and 3D structure analysis.
- Protein-protein interaction analysis of BpDapF.
- Molecular docking studies to assess binding interactions with potential inhibitors.
- Biochemical assays to determine binding energies.
Main Results:
- In silico analysis provided insights into BpDapF's structure and interactions.
- Docking studies identified key amino acid residues in the phosphate-binding loop involved in ligand binding.
- Limonin, Ajmalicine, Clinafloxacin, Dexamethasone, and Tetracycline showed promising binding affinities to BpDapF, with Limonin exhibiting the highest ( -8.8 kcal/mol).
Conclusions:
- BpDapF is a viable drug target for combating B. pertussis.
- Several compounds, particularly Limonin, demonstrate potential as BpDapF inhibitors.
- These findings pave the way for developing new anti-pertussis therapeutics by targeting the lysine biosynthesis pathway.
