Computational protocol: In silico study on Penicillin derivatives and Cephalosporins for upper respiratory tract bacterial pathogens

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[…] PBP was thought to be essential for the synthesis of bacterial cell wall. All types of the PBPs (PBP1a, PBP1b, PBP2a, PBP2b, PBP2x, PBP3, PBP4, PBP5 and PBP6) were selected for this study. 3-Dimensional (3D) structures of the PBPs were obtained from Protein Data Bank (PDB) (Berman et al. ). 3D structures of PBPs were visualized through PyMOL viewer (Lill and Danielson ). Co-crystallized ligands were identified and removed from the target proteins then water molecules removed and H atoms were added to the structure and minimizations were performed using Swiss pdb viewer (Guex and Peitsch ). The 3D coordinates of the Penicillin derivatives and Cephalosporins were obtained from NCBI PubChem Compound database (Li et al. ) and constructed using chemsketch (Li et al. ). Hydrogen atoms were added to all the structures and gasteiger atomic partial charges were computed. A geometry optimization of all the compounds was performed using chimera (Pettersen et al. ) for flexible conformations of the compounds during the docking.PDB ID of every PBP was depicted in Table  and two-dimensional structures of Penicillin derivatives and Cephalosporins are shown in Fig. .Fig. 1 [...] The catalytic binding site was believed to be a small region, a cleft or pocket, where lead molecules can bind to stimulate the target protein and produce the desirable effect. Thus, recognizing the catalytic binding site residues in the protein structure was of high importance in computer-aided drug designing. Identification of accurate catalytic binding site was difficult because the target proteins were capable of undergoing conformational changes (Liao and Andrews ). Qsite finder (Laurie and Jackson ) recognizes the possible ligand binding sites using the van der Waal’s probes and interaction energy. In the present study, Qsite finder was employed for locating the active sites in PBP1a, PBP1b, PBP2a, PBP2b, PBP2x, PBP3, PBP4, PBP5 and PBP6 proteins. [...] iGEMDOCK (A Generic Evolutionary Method for molecular DOCKing) automated docking program (Yang and Chen ). iGEMDOCK integrated the structure-based virtual screening, molecular docking, post screening analysis and visualization steps. We selected all types of PBPs (PBP1a, PBP1b, PBP2a, PBP2b, PBP2x, PBP3, PBP4, PBP5 and PBP6) to carry out the structure-based virtual screening study of penicillin derivatives and Cephalosporins. The 3D coordinates of each therapeutic target protein and ligand molecules were implemented through the GEMDOCK graphical environment interface. Before docking, the output path was set. GEMDOCK default parameters included the population size (n = 200), generation (g = 70) and number of solutions (s = 10) to compute the probable ligand binding mechanism for each target protein. Then the docking run was started using GEMDOCK scoring function. After docking, the individual binding pose of each ligand was observed and their binding affinity with the target proteins was analyzed. In the post docking screening the best binding pose and total energy of each ligand was analyzed. The details of best binding pose and total energy values were saved in output folder. Protein–ligand binding site was analyzed and visualized using PyMOL (Lill and Danielson ). [...] The automated docking studies were carried out using Auto-Dock version 4.0 (Morris et al. ). 3D structure of each PBPs were implemented through the graphical user interface AUTODOCKTOOLS (ADT 1.4.6). The graphical user interface AUTODOCKTOOLS was performed to set up the enzymes: all hydrogens were added, Kollman United Atoms charges loaded and non-polar hydrogens were merged to carbon atoms. The initial parameters and van der Waals well depth of 0.100 kcal/mol for macromolecules, generated PDBQT files were saved. The 3D structures of ligand molecules were constructed, optimized, and converted into Mol2 file format with the help of the chimera. The charges of the non-polar hydrogen atoms are assigned to the atom to which the hydrogen is attached. The resulting files were saved as PDBQT files. The drug binding site for the ligands on PBP1a, PBP1b, PBP2a, PBP2b, PBP2x, PBP3, PBP4, PBP5 and PBP6 were identified using Qsite finder online server. The grid point was set at the ligand binding site in each one of the obtained PDB structures. AUTODOCK 4.0 was performed for all docking calculations. The AUTODOCKTOOLS was used to generate the grid parameter files and docking parameter files. The docking parameters were also used to calculate docking scores for β-lactam antibiotics and Penicillin derivatives. Protein–ligand docking calculations were carried out on PBPs. Lamarckian genetic algorithm (Morris et al. ) was used to generate possible protein–ligand binding conformations. [...] The molinspiration (Jarrahpour et al. ) server was used to predict the ADME properties of the antibiotics. It predicted both physiochemical and pharmacological properties. Smiles (Simplified Molecule Input Line Entry Specification) of the antibiotics was submitted. It predicted the properties of the drug such as molecular volume, number of hydrogen bond donors and acceptors, LogP and rotatable bonds. It provided high-speed molecular properties calculated and drug likeness for a given compound. The acceptability of the analogs is evaluated based on Lipinski’s rule of 5 (Lipinski et al. ), which is essential for structure-based drug design. […]

Pipeline specifications

Software tools iGEMDOCK, PyMOL, AutoDock, QSite, Molinspiration
Applications Drug design, Protein interaction analysis
Diseases Infection, Meningitis, Haemophilus, Respiratory Tract Infections