Homology modeling module of MODELLER was assembled in Discovery Studio 2.0, Accelrys was used. The template structure of ERα66 was obtained from the Protein Data Bank. ERα36 lacks the ligand-binding domain residues aa482-595 but retained aa302-465 of ERα66. To model the structurally conserved core of ERα36, we deleted the corresponding regions from the mutant protein. The structure of 4-OHT was modeled by the sketch tool of Discovery Studio 2.0, Accelrys. The complexes of ERα36 ligand-binding domain and the ligand were built by CDOCKER of Discovery Studio 2.0, Accelrys. The docking procedure was implemented as Chemistry at HARvard Macromolecular Mechanics for configurational exploration with a rapid energy evaluation using grid-based molecular affinity potentials. A rectangular volume was defined around the ER36 ligand-binding cavity which was presumed flexible resulting in 20 best conformations according to the free energy of binding. The conformation of 4-OHT with the maximal free energy binding was selected. The superimposed structure and molecular diagrams of the complexes of 4-OHT and ERα36 were drawn with Profiles-3D.
Discovery studio 2
Manufactured by Dassault Systèmes
Sourced in United States
Discovery Studio 2.5 is a comprehensive software package for molecular modeling, simulation, and analysis. It provides a suite of tools for studying the structure and function of biomolecules, including proteins, nucleic acids, and small molecules. The software offers a range of features for tasks such as protein structure prediction, ligand docking, and virtual screening.
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Lab products found in correlation
Chembiodraw ultra 13, by Revvity Signals Software (6 mentions)
Discovery studio, by Dassault Systèmes (2 mentions)
Chembiodraw ultra 11, by Revvity Signals Software (2 mentions)
Discovery studio 4, by Dassault Systèmes (2 mentions)
Sybyl x 2, by Tripos (2 mentions)
Tools version 1, by AutoDock (1 mentions)
Protonate 3d tool, by Chemical Computing Group (1 mentions)
Pymol software, by DeLano Scientific (1 mentions)
Sketch module, by Tripos (1 mentions)
Isoniazid, by Merck Group (1 mentions)
Rifampicin, by Merck Group (1 mentions)
Avance 2 500 spectrometer, by Bruker (1 mentions)
6538 q tof mass spectrometer, by Agilent Technologies (1 mentions)
Insight 2 discover, by Dassault Systèmes (1 mentions)
Prepwizard, by Schrödinger (1 mentions)
Origin 9, by OriginLab (1 mentions)
Pymol software, by Schrödinger (1 mentions)
163 protocols using discovery studio 2
1
Homology Modeling and Ligand Docking of Estrogen Receptor Alpha Isoform
2
Molecular Docking of Fomesafen and Compound 4i
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The three-dimensional structures of fomesafen and compound 4i were modelled using SYBYL-X 2.0. Subsequently, Gasteiger–Huckel charges were also determined during optimization of the molecule. Molecular docking was performed using CDOCKER modules in Discovery Studio 2.5 (BIOVIA Inc., San Diego, CA, USA). The parameters are used in the molecular docking study with the default docking setting (Top Hits:10; Random Conformations: 10; Dynamics Steps: 1000; Forcefield: CHARMm; Ligand Partial Charge Method: Momany-Rone; Final Minimization: Full Potential). -CDOCKER ENERGY (compounds 4i ): 11.339 kcal/mol; -CDOCKER ENERGY (fomesafen): 31.0016 kcal/mol. The crystal structure of PPO (PDB ID, 1SEZ) was obtained from the Protein Data Bank. Water and other small molecules were expunged using Accelrys Discovery Studio 2.5 to reduce the influence of certain cocrystallized substances in the protein. A known ligand was used to determine the active site of PPO. The evaluation index for the binding energy of the small molecule-receptor protein complex and the strongly negative performance indicates a highly stable structure.
3
Docking Study of JAK Kinase Inhibitors
4
CXCR4 Protein Structure Docking Analysis
5
Pharmacophore-Based Virtual Screening for Chk2 Inhibitors
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After examining 15 diversity rank/score graphs, the PhModels A and B determined from the best prediction result pair were used to screen the NCI database for new Chk2 inhibitor candidates. Under the PhModel, pharmacophore hypothesis screening can be used to screen small molecule database to retrieve the compounds as potential inhibitors that fit the pharmacophoric features. In this study, the “Search 3D Database protocol” with the Best/Fast/Casear Search option in Accelrys Discovery Studio 2.1 was employed to search the NCI database with 260,071 compounds. We could filter out and select the compounds in the NCI database based on the estimated activity and chemical features of PhModel.
6
Structural Modeling and Validation of WSTF PHD_EL5 RING Finger
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The structure modeling was performed using the I-TASSER server (as “Zhang Server”), which consists of multiple threading alignments and iterative template fragment assembly simulations18 (link)34 (link). The I-TASSER program was ranked as the best server in the Critical Assessment of protein Structure Prediction experiments. The server generates the most accurate structural predictions via a state-of the-art process. The quality of the predicted structures was evaluated by a confidence score (C-score), and a C-score of >−1.5 denotes a correct fold. The template modeling score (TM-score) describes the topological similarity between the predicted model and the native structure. A TM-score of >0.5 indicates protein pairs with similar folds as well as a more accurate model prediction18 (link). The amino acid sequence of the WSTF PHD_EL5 RING finger (Figure 1 ) was subjected to the I-TASSER server, and the obtained structure was validated using PROCHECK23 . The program Discovery Studio 2.1, San Diego: Accelrys Software Inc., was used to calculate the Connolly surface and prepare drawings of the structures32 (link).
7
Docking Analysis of AChE and BChE Enzymes
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The docking of the studied compounds was performed using the Accelrys DiscoveryStudio 2.1 CDOCKER docking protocol and CHARMm force field. For the structural model of AChE, we used a crystal structure deposited in the Protein Data Bank, PDB ID 1B4140 (link) and PDB ID 2PM8 as a model for usual BChE41 . Models for atypical and fluoride-resistant BChE were constructed using the 2PM8 structure as a model in which Asp70 was replaced with Gly as a model for atypical BChE, and Thr243 with Met or Gly390 with Val as models of fluoride-resistant BChE. All of the constructed models were minimised using the CHARMm force field according to the docking protocol described previously9 (link),42 (link). As a result of molecular docking, a set of 20 possible poses per one compound and enzyme pair was analysed and the pose with the highest CDOCKER interaction energy was selected for further analysis.
8
Pharmacophore Modeling for Chk2 Inhibitors
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The workflow of PhModel generation for Chk2 inhibitors was shown in Figure 3 . In this study, we used the HypoGen program [37 ] in Accelrys Discovery Studio 2.1 to generate PhModels. At the initial step, 3D conformations of the training set inhibitors were generated by using “3D-QSAR Pharmacophore Generation protocol” with the Best, Fast, and Caesar generating algorithms, respectively, based on the CHARMm-like force field. The conformational-space energy was constrained ≤20 kcal/mol which represented the maximum allowed energy above the global minimum energy. For each training set inhibitor, the number of the diverse 3D conformations was set to ≤255. All other parameters were set as default values. Following the above rules, the 3D conformations were generated, and then we can construct the PhModel by using “Ligand Pharmacophore Mapping protocol.” Each of the ten PhModels using HypoGen Best, Fast, and Caesar algorithms were generated in this study.
9
Conformational Generation and Culling
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The 3D conformations of the training set were generated by molecular dynamics modeling with CHARMm force field parameters [37] using Discovery Studio 2.1 software (Accelrys, Inc., San Diego, CA). The procedure involved the following steps: (i) Conjugate-gradient minimization in torsion space, (ii) Conjugate-gradient minimization in Cartesian space, and (iii) Quasi-Newton minimization in Cartesian space. The conformational-space energy, which corresponds to the maximum energy allowed above the global energy minimum, was constrained to ≤20 kcal/mol. The generated by this stage was kept and performed the structural comparison. If the RMSD (Å) of any of the two snapshots are less than 0.2, compounds were considered as duplicate structure and were removed, and the maximum allowable number of 3D conformations for each inhibitor was restricted to 255.
10
Heterocyclic Derivatives Preparation and Optimization
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The selected heterocyclic derivatives from various literature resources
[21 (link),22 (link), 23 (link),24 (link), 25 (link),26 (link),27 (link)] were drawn using ACD/ChemSketch (12.0).Figure 1 shows the 2D structure of the
sketched compounds. Further imported into Accelrys Discovery Studio 2.1 and
ligand preparation with constraint parameters such as consistency of ionization
states, tautomer and isomer generation, removal of duplicate structures,
conversion of 2D to 3D structures was done. By applying the forcefield CHARMm,
minimization was carried out with the smart minimizer algorithm till it
satisfied with the convergence gradient of 0.001 kcal mol-1, to attain the
lowest energy conformers which were taken for further evaluation.
[21 (link),22 (link), 23 (link),24 (link), 25 (link),26 (link),27 (link)] were drawn using ACD/ChemSketch (12.0).
sketched compounds. Further imported into Accelrys Discovery Studio 2.1 and
ligand preparation with constraint parameters such as consistency of ionization
states, tautomer and isomer generation, removal of duplicate structures,
conversion of 2D to 3D structures was done. By applying the forcefield CHARMm,
minimization was carried out with the smart minimizer algorithm till it
satisfied with the convergence gradient of 0.001 kcal mol-1, to attain the
lowest energy conformers which were taken for further evaluation.
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