A homology model of KL2 was generated using the program Molecular Operating Environment (MOE) (Chemical Computing Group) with the crystal structure of KL1 domain46 as a template. We defined surface residues as residues with a solvent-accessible surface area larger than 10 Å2 and selected all surface residues on KL1 structure and KL2 model in PyMOL Molecular Graphics System, version 1.7 (Schrödinger). All structural figures were prepared using PyMOL.
Molecular operating environment
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Molecular Operating Environment (MOE) is a comprehensive software package for molecular modeling and computational chemistry. It provides a suite of tools for molecular structure building, visualization, and analysis. MOE supports a wide range of file formats and integrates several computational chemistry methods, enabling users to perform tasks such as molecular docking, homology modeling, and molecular dynamics simulations.
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Lab products found in correlation
27 protocols using molecular operating environment
1
Homology Modeling and Surface Analysis of KL2
2
Pharmacophore Model for GES-5 Inhibitors
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A pharmacophore for GES-5 inhibitors was derived in an analogous way as done previously for KPC-2 [21 (link)]. The structure comparison of GES-5 and KPC-2 was performed using the Molecular Operating Environment (MOE; Chemical Computing Group, Montreal, QC, Canada) and PyMOL (Schrödinger, LLC, New York, NY, USA). The published structures of GES-5 (PDB code 4GNU and 4H8R) and our in-house structure were aligned with the structure of KPC-2 (PDB code 3RXW) to identify key interactions. The final pharmacophore was based on the apo-crystal structure of GES-5, which we have solved for this project (PDB code 6TS9), and the ligand 0JB of CTX-M-9 β-lactamase (PDB code 4DE0). It contained the same features as our previous pharmacophore for KPC-2, namely a hydrogen-bond acceptor feature for interactions with Ser125, Thr230 and Thr232, a hydrophobic π-stacking feature with Trp99 and a hydrogen bond acceptor feature for interaction with Asn127 (Figure 2 a). The interactions to Thr230 and Thr232 were set as mandatory for filtering the obtained docking hit list.
3
Computational Modeling of PSD-95 Protein Interactions
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All the computational procedures were carried out through the Molecular Operating Environment (MOE) version 2014.0901 from the Chemical Computing Group. The Amber99 forcefield61 with the Generalized Born implicit solvation method62 was used for all the computational tasks.
The crystallographic structure of the PDZ3 domain of rat PSD-95 co-crystallized with a C-terminal peptide derived from the CRIPT protein (PDB ID: 1BE9)34 (link) was downloaded and submitted to the Structure Preparation procedure. The binding free energy between PSD-95 and the CRIPT peptide was computed through the MOE LigX procedures, useful to minimize the crystallographic structure and to estimate the binding affinity through the forcefield-based GBVI/WSA dG scoring function, which estimates the free energy of interaction. The complex between the PSD-95 PDZ3 domain and the C-terminus of Rph3A was obtained by mutating the CRIPT peptide into HVSSD primary structure with the Protein Design module. The binding free energy was computed with the MOE LigX as above.
The crystallographic structure of the PDZ3 domain of rat PSD-95 co-crystallized with a C-terminal peptide derived from the CRIPT protein (PDB ID: 1BE9)34 (link) was downloaded and submitted to the Structure Preparation procedure. The binding free energy between PSD-95 and the CRIPT peptide was computed through the MOE LigX procedures, useful to minimize the crystallographic structure and to estimate the binding affinity through the forcefield-based GBVI/WSA dG scoring function, which estimates the free energy of interaction. The complex between the PSD-95 PDZ3 domain and the C-terminus of Rph3A was obtained by mutating the CRIPT peptide into HVSSD primary structure with the Protein Design module. The binding free energy was computed with the MOE LigX as above.
4
Computational Chemistry Descriptors Protocol
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AlvaDesc (Alvascience Srl, Lecco, Italy) software was used to calculate Dragon [13 ] descriptors (Formerly DragonX), Molecular Operating Environment (MOE, Chemical Computing Group Inc, Montreal, QC, Canada) software was used to calculate MOE descriptors and Molecular Discovery Software (Molecular Discovery, Borehamwood, UK) software was used to calculate VolSurf+3D descriptors [14 (link)]. Prior to descriptor calculation, 3D conformers were generated using Corina (Molecular Networks GmbH, Nürnberg, Germany and Altamira LLC, Columbus, OH, USA) followed by energy minimization using MMFF94 force field, embedded in MOE software.
WEKA [39 ] (version 3.8, Waikato, New Zealand) platform was used for feature selection and for the development and optimization of regression algorithms.
ACD/Labs LC Simulator (ACD/Labs, Toronto, ON, Canada) version 2019 was used to carry out two-dimensional resolution optimisation.
WEKA [39 ] (version 3.8, Waikato, New Zealand) platform was used for feature selection and for the development and optimization of regression algorithms.
ACD/Labs LC Simulator (ACD/Labs, Toronto, ON, Canada) version 2019 was used to carry out two-dimensional resolution optimisation.
5
Molecular Modeling and Docking Analysis
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All the molecular modeling calculations and docking simulation studies were performed using the Molecular Operating Environment (MOE 2014.0901, 2014; Chemical Computing Group, Canada) software. All MOE minimizations were performed until an RMSD gradient of 0.01 kcal/mol/Å with the force field (Amber10:ETH) and gas phase solvation to calculate the partial charges automatically. Before simulations, the protein was protonated using the LigX function and the monomer was identified. Induced fit docking simulation was performed initially to predict the active site using C18 ceramide as a flexed ligand. Triangle matching with London dG scoring was chosen for initial placement, then the top 30 poses were refined using force field (Amber10:ETH) and Affinity DG scoring. The top pose from this simulation was analyzed and further used as a reference for the docking simulation of the newly isolated compounds 1 and 2 . The output database dock file was created with different poses for each ligand and arranged according to the final score function (S), which is the score of the last stage that was not set to zero.
6
Screening Natural Compounds for CD73 Inhibition
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The docking software Molecular Operating Environment (MOE) purchased from Chemical Computing Group Inc (Montreal, QC, CA). The CD73 protein structure (accession code: 4H2G) was downloaded from Protein Data Bank and optimized for hydrogens and lone pairs within MOE. Natural compound structures were downloaded as potential ligands from PubChem in the SDF file format. The docking score, protein-ligand interactions, and the respective energies released from the interaction were generated and recorded using MOE Align/Superpose functions.
7
Molecular Modeling Workflows on Linux
8
Molecular Docking of Sunitinib on CDK2
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The molecular docking studies were performed (Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Egypt) using Molecular Operating Environment (MOE 2019.01, 2019; Chemical Computing Group, Canada) as the computational software. The three-dimensional structures and conformations of the enzyme, cyclin-dependent kinase enzyme (CDK2) in complex with sunitinib (PDB ID: 3TI1 ), was acquired from the Protein Data Bank (PDB) web site.40 The binding affinity of the docked molecules was expressed as binding score (S, kcal mol−1). Briefly, docking of the investigated molecules was performed in four steps: preparation of the 3D structure of the target, preparation of the ligands, running docking, and interpretation of the results. Docking was performed using the default settings of the MOE program [Placement, triangular Matcher; Rescoring 1, London dG with retain = 30; Refinement, Forcefield; Rescoring 2, GBVI/WSA dG with retain = 30]. The key amino acids involved in the interaction of sunitinib with CDK2 in the co-crystalized target are Ile10, Glu81, Leu83, Gln85 and Asp86. Re-docking of sunitinib was performed to accurately evaluate the efficiency of the method (rmsd = 2).
9
Structural Analysis of ClfB Protein
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ClfB structures were downloaded from the Protein Data Bank (34 (link)). The structures for ClfB, PDB ID 4F20 , 4F1Z and 4F27 , were used (15 (link)). ClfB structures and their ligands were superposed using the align/superpose function in the Molecular Operating Environment (Chemical Computing Group, Montreal, Canada). All ligands studied were prepared for docking using the “wash” function and all tautomers enumerated. CCPDB structures, 4F20 (ClfB) (15 (link)) and 2VR3 (ClfA) (13 (link)) were used as the targets and prepared for docking using the protonate 3D function with default parameters. The peptide ligand was used to define the binding site for docking using macromolecule residues within 4.5 Å of the peptide ligand. Docking was performed using the Triangle Matcher function for placement and London delta G scoring, storing 30 poses. Rigid receptor was used for refinement and GBVI/WSA delta G scoring for the final poses.
10
Structural Analysis of ClfB Protein
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ClfB structures were downloaded from the Protein Data Bank (34 (link)). The structures for ClfB, PDB ID 4F20 , 4F1Z and 4F27 , were used (15 (link)). ClfB structures and their ligands were superposed using the align/superpose function in the Molecular Operating Environment (Chemical Computing Group, Montreal, Canada). All ligands studied were prepared for docking using the “wash” function and all tautomers enumerated. CCPDB structures, 4F20 (ClfB) (15 (link)) and 2VR3 (ClfA) (13 (link)) were used as the targets and prepared for docking using the protonate 3D function with default parameters. The peptide ligand was used to define the binding site for docking using macromolecule residues within 4.5 Å of the peptide ligand. Docking was performed using the Triangle Matcher function for placement and London delta G scoring, storing 30 poses. Rigid receptor was used for refinement and GBVI/WSA delta G scoring for the final poses.
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