Molecular docking analysis of compound 5k with the ATP active binding pockets of CDK2, EGFR, Her2, and VEGFR2 were studied according to the previously described methods [34 (link),37 (link)]. The X-ray crystal structures of the EGFR kinase domain bound to erlotinib (PDB ID: 4HJO), the VEGFR2 kinase domain bound to sorafenib (PDB ID: 4ASD), the kinase domain of human Her2 bound to TAK-285 (PDB ID: 3RCD), and the CDK2 kinase bound to sunitinib were acquired from The Protein Data Bank (http://www.rcsb.org , (accessed on 5 June 2023). For docking studies, Discovery Studio, AutoDock Tools, Vina, and PyRx (The Scripps Research Institute, La Jolla, CA, USA) software programs were employed. First, all additional molecules, such as water, ligands, and sulfate, were removed from the downloaded protein crystal structures and the obtained files were saved as PDB format. Second, the previously saved files were converted to PDBQT format after adding polar hydrogens by using AutoDock Tools. Third, the co-crystallized ligands were separated by Discovery Studio saved in a PDB file and converted to PDBQT file by using AutoDock Tools. Finally, PyRx was utilized to conduct the docking simulations. The best pose of compound 5K superimposed with the reference standard positive control was exploited to investigate the possible binding interactions with the target kinase enzymes.
Discovery studio
Manufactured by AutoDock
Sourced in United States
Discovery Studio is a comprehensive software platform for molecular modeling and simulation. It provides a suite of tools for structure-based drug design, including molecular visualization, protein structure prediction, and virtual screening. The software enables researchers to analyze and interpret complex molecular data, supporting the drug discovery process.
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Lab products found in correlation
8 protocols using discovery studio
1
Molecular Docking Analysis of Compound 5k
2
Molecular Docking of HLA-Epitope Complexes
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Before docking, the 3D structure of the epitope RTFAMSSER was built using PEP-FOLD3 [109 (link)], and the PDB (Protein Data Bank) structure of the HLA-C*03:03 (PDB ID: 1EFX) was retrieved from the RCSB database [110 (link)] where it was complexed with human natural killer cell receptor KIR2DL2. Then the complex was opened using Discovery Studio [111 ] to remove the receptor and recover the simplified HLA-C*03:03.
Autodock Vina [112 (link)] was used to calculate the binding energy between the target epitope and the corresponding HLA. The docked complex was visualized using PyMol [113 ] and UCSF Chimera [114 (link)].
However, the rest of the epitopes and HLA alleles were also subjected to molecular docking simulation following the similar procedure in order to estimate the relation between the docking score, IC50 value, and combined score of proteasome score, TAP score, MHC-I score, processing score.
Autodock Vina [112 (link)] was used to calculate the binding energy between the target epitope and the corresponding HLA. The docked complex was visualized using PyMol [113 ] and UCSF Chimera [114 (link)].
However, the rest of the epitopes and HLA alleles were also subjected to molecular docking simulation following the similar procedure in order to estimate the relation between the docking score, IC50 value, and combined score of proteasome score, TAP score, MHC-I score, processing score.
3
Docking Simulation of VEGFR2 and EGFR Inhibitors
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The protein crystal structure data was obtained from the RCSB Protein Databank. The 3D-crystal structures used for docking are 4AGD (VEGFR2 crystal structure data of juxtamembrane and kinase domain in complex with sunitinib) and 2ITY (EGFR crystal structure data of kinase domain in complex with gefitinib). Software programs used for docking simulations were Discovery Studio, AutoDock Tools, Vina, and PyRx (The Scripps Research Institute, La Jolla, CA). First, using Discovery Studio, the protein crystal structure data was processed by eliminating all extra molecules such as water, ligand, and sulfate. The processed data was saved as in PDB file format. Second, polar hydrogens were introduced using AtuoDock Tools and the file was saved in PDBQT format. Third, the co-crystallized ligands were isolated and saved in PDB format using Discovery Studio. Compounds 16 and 18 were also saved in PDB file format. Grid box was used to suppress non-specific binding predictions, reduce processing time, and pinpoint the docking size and dimension. Finally, docking simulations were performed using PyRx; the lowest energy poses of the compounds were and compared with the co-crystallized ligand poses.
4
Molecular Docking of Ligands
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The target proteins were prepared by removing the water molecules using Discovery Studio. The parameters for docking were set up by using the graphical user interface (GUI) of AutoDock Tools [62 (link)]. The preparation of the target protein structure involves the addition of hydrogen atoms and formal charges. The number of rotatable bonds and determination of root for the ligand were set to default. Later, molecular docking was performed using AutoDock 4.2. The AutoGrid4 program of AutoDock allowed the generation of grid maps for target proteins embedded in a three-dimensional grid of manually set parameters (Table 9 ).
The binding energies between the target protein and ligand were calculated by running the AutoDock4 program using pre-set grid maps. The result analysis was performed using the GUI of AutoDock Tools and Discovery Studio. The binding energies for various conformations of the ligand with the target proteins were determined, and the best conformation was chosen based on the binding energy and the number of hydrogen bonds that they formed with the protein.
The binding energies between the target protein and ligand were calculated by running the AutoDock4 program using pre-set grid maps. The result analysis was performed using the GUI of AutoDock Tools and Discovery Studio. The binding energies for various conformations of the ligand with the target proteins were determined, and the best conformation was chosen based on the binding energy and the number of hydrogen bonds that they formed with the protein.
5
Structural Analysis of YAP-Alisol A Binding
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The crystal structure of YAP was obtained from the protein data bank (PDB, http://www.rcsb.org/ , ID: 4rex). Crystal structure of each protein was selected based on the best resolution available. PubChem (https://pubchem.ncbi.nlm.nih.gov/ ) was used to obtain the three-dimension (3D) structure of alisol A (MOL000850). AutoDock Vina and Discovery Studio software were used for the docking simulations and calculations. The value of root mean square deviation (RMSD) was calculated using PyMOL. The prediction of binding mode was selected with RMSD below 2.0 Å.
6
Protein-Ligand Docking Simulations
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The PDB Data Bank (http://www.rcsb.org , (accessed on 25 December 2022) was utilized to obtain the X-ray crystal structures of the EGFR kinase domain in complex with erlotinib (PDB ID: 4HJO), the VEGFR2 kinase domain in complex with sorafenib (PDB ID:4ASD) and the kinase domain of human HER2 (PDB ID: 3RCD) in complex with lapatinib. The Discovery Studio, AutoDock Tools, Vina, and PyRx (The Scripps Research Institute, La Jolla, CA) software programs were used for docking simulations. First, the protein crystal structures were prepared by removing all additional molecules such as water, ligands, and sulfate. The generated data was saved in PDB file format. Second, AutoDock Tools was used to add polar hydrogens to the previous file saved in the PDB format, and the data were saved in PDBQT format. Third, using Discovery Studio, the co-crystallized ligands were separated from the protein structure and saved in a PDB file. Compound 15 was also saved in a PDB file. A grid box was employed to eliminate nonspecific binding interactions and minimize docking time. Finally, PyRx was used to perform the docking simulations, while the lowest energy pose of compound 15 superimposed with the co-crystallized ligands was used to study the interaction with the kinase enzyme.
7
Molecular Docking of Selective COX-2 Inhibitors
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The protein crystal structure was obtained from the RCSB Protein Databank. The 3D-crystal structure used for docking was 5KIR, cyclooxygenase-2 (prostaglandin synthase-2) complexed with the selective inhibitor rofecoxib, with a resolution of 2.697 Å. Discovery Studio, AutoDock Tools, Vina, and PyRx (The Scripps Research Institute, La Jolla, CA, USA) software programs were used for molecular docking. Using Discovery Studio, the protein crystal structure was processed by removing water, ligands, and sulphate molecules. The protein was then saved as a PDB file format. Second, polar hydrogens were added using AutoDock Tools, and the file was saved in PDBQT format. Third, the original ligand was isolated and saved as a PDB using Discovery Studio. Compounds 5a and 8d were also saved in PDB file format. Finally, docking was performed by PyRx, and the docking scores were obtained.
8
CFTR Structure Analysis by Cryo-EM and Molecular Modeling
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The CFTR structure obtained from electron cryomicroscopy (cryo-EM) was used as a reference molecule (Protein Data Bank ID: 5UAK.pdb; [18 (link)]), and all possible pockets were identified using PrankWeb [19 (link)]. The MANORAA platform was used to sketch and obtain protein-ligand interacting motifs based on the three-dimensional coordinates from the Protein Data Bank (PDB) [20 (link)]. HyperChem was used to correct bond order and hydrogen atoms of the ligand CFTRinh-172 and genistein. Conformational search and energy minimization were performed using Molecular Mechanics based on Steepest Descent algorithm [21 (link)]. Biased docking was performed by using Biovia Discovery Studio and Autodock Vina 1.2.0 [22 ,23 (link)].
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