The three dimensional protein structure of the human DDX3 receptor (PDB ID 2I4I) with resolution of 2.20 Å complexed with AMP ligand and a total of 1, 22,163 molecules were retrieved a Protein Data Bank (PDB) and the ZINC natural database (https://zinc.docking.org/browse/catalogs/natural-products ) respectively. Protein preparation wizard implemented in Maestro (Maestro, v. S., LLC; New York, NY, USA) was used to prepare the protein. Ligands were filtered to remove undesirable non-lead like compounds using the program FILTER 2.0 in Open Eye Software. The outcome compounds were passed through Pan-assay interference compounds (PAINS) filter (http://cbligand.org/PAINS/ ) to identify a number of substructural features to minimize the screening time for the active compounds. Finally filtered compounds were imported into Lig Prep tool, which is used for preparing ligands by optimizing geometries through OPLS-2001 Force Field44 . All possible confirmations of ligand were generated at physiological PH ± 4 to ± 7. The generated conformers range from 1 to 100 depends upon the type of ligand. Glide XP docking output post-viewer file was used to calculate the binding free energy values of the receptor and the top 10 molecules by Prime/MM-GBSA module in the Schrödinger suite.
Prime mm gbsa module
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The Prime MM-GBSA module is a software tool designed to perform molecular mechanics-Generalized Born surface area (MM-GBSA) calculations. MM-GBSA is a computational method used to estimate the free energy of binding between a ligand and a target protein. The Prime MM-GBSA module provides a streamlined workflow for carrying out these calculations, which are important in drug discovery and development processes.
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24 protocols using prime mm gbsa module
1
Molecular Docking Analysis of DDX3 Receptor
2
Molecular modeling of CIN-HPβCD complexes
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The molecular modeling studies of CIN with HPβCD in the presence and absence of TA were carried out using the Schrödinger software suite (Schrödinger, LLC, New York) in the Maetsro module (version 11.1).
Structure collection: CIN and TA structures were drawn and optimized using Ligprep module. Finally, the geometry optimization was carried out using the OPLS2005 force field. HPβCD structure was drawn by adding 2‑hydroxy propyl chain to native βCD structure imported from PDB (PDB ID:1BFN ). Geometry of HPβCD was optimized using Macro model module.
Generation of supramolecular inclusion complex models: The Glide module was used for generating HP-β-CD inclusion complexes. The grid was generated using the Glide Grid Generation panel in Glide. For generating HPβCD binary supramolecular inclusion complex, CIN was docked with standard precision (SP) mode on HPβCD. The ternary supramolecular inclusion complex was generated by docking the binary inclusion complex with TA in SP mode.
Binding affinity calculation: The binding affinity “ΔG” was calculated using the Prime MM-GBSA module (version 4.5, Schrödinger), which calculates the free energy change upon formation of the complex in comparison to total individual energy based on change in the solvent accessible surface area [27] (link).
Structure collection: CIN and TA structures were drawn and optimized using Ligprep module. Finally, the geometry optimization was carried out using the OPLS2005 force field. HPβCD structure was drawn by adding 2‑hydroxy propyl chain to native βCD structure imported from PDB (PDB ID:
Generation of supramolecular inclusion complex models: The Glide module was used for generating HP-β-CD inclusion complexes. The grid was generated using the Glide Grid Generation panel in Glide. For generating HPβCD binary supramolecular inclusion complex, CIN was docked with standard precision (SP) mode on HPβCD. The ternary supramolecular inclusion complex was generated by docking the binary inclusion complex with TA in SP mode.
Binding affinity calculation: The binding affinity “ΔG” was calculated using the Prime MM-GBSA module (version 4.5, Schrödinger), which calculates the free energy change upon formation of the complex in comparison to total individual energy based on change in the solvent accessible surface area [27] (link).
3
STING Ligand Docking and Evaluation
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The crystal structure of STING complex (PDB ID: 6MXE) was taken from a Protein Data Bank entry and used as the starting point. Protein was prepared using the Protein preparation of Maestro and split into chain A and chain B. We generated a binding site in the LBD of STING monomer based on the original ligand (Merck-18) using Receptor Grid Generation. We used the SP precision of Glide-docking for the molecular docking part, allowing compound 11 to generate at most 20 poses. We ultimately produced 16 bound conformations (all in the bottom pocket), and tested the binding free energy of the complexes using the Prime MM-GBSA module in Schrödinger’s software. Furthermore, based on the docking score, glide emodel score, and MMGBSA dG Bind score, we selected the optimal conformation scored first in two and ranked third in one (seen in Table S2 ). Finally, we merged the best conformations of the A and B chains to obtain the complete docking structure.
4
Screening Bis-pyrimidine Derivatives Against HRas
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Once the target protein is identified as GTPase HRas, was used for screening of bis-pyrimidine derivatives library was screened through GTP binding site using extra precision (XP) docking module of Schrodinger v9.6. XP module performs docking the compounds with better precision and accuracy. The dataset size goes smaller as the docking accuracy increases at each stage [17 (link)]. The endogenous ligand Guanosine triphosphate (GTP) was used as docking control and binding energy was also calculated (PrimeMM-GBSA module) Schrodinger v9.6 [19 (link)].
5
Calculating Binding Affinities via MM/GBSA
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Following MD simulation of selected protein–ligand complexes, end point based binding free energy method, i.e., Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) was applied to the extracted poses at every 10 ns from each simulation trajectory to calculate the mean binding free energy under default parameters via Prime MMGBSA module of the MM/GBSA protocol in Schrödinger suite (Schrödinger Release 2018.3: Prime, Schrödinger, LLC, New York, NY, 2018). In this method, extracted poses were refined by deletion of solvent molecules and ions, as reported earlier53 (link). Finally, net free binding energy (ΔG) was calculated using the following Eq. (1 ). where ΔGbind denotes the binding free energy, ∆ Gcomplex, indicates the free energy of the complex, ∆ Greceptor and ∆ Gligand exhibits the energy for receptor and ligan, respectively.
6
Computational Binding Energy Analysis
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The Prime MM-GBSA module in the Schrodinger software was employed to determine the free energy associated with the binding of ligands to a protein. Which is determined by the following equation:
where ΔE is the free binding energy, Ec is the target/ligand complex energy, ER is the receptor energy and EL is the ligand energy. The calculations were performed using the OPLS4 force field and the VSGB solvation model [20 (link)]. MM-GBSA calculations were carried out on the highest-scoring drugs obtained from docking studies, which exhibited superior scores with three specific protein targets. To compare the results of the MM-GBSA analysis, a similar screening approach was utilized for approved inhibitors targeting CDK4/6 (abemaciclib) and aromatase (letrozole).
where ΔE is the free binding energy, Ec is the target/ligand complex energy, ER is the receptor energy and EL is the ligand energy. The calculations were performed using the OPLS4 force field and the VSGB solvation model [20 (link)]. MM-GBSA calculations were carried out on the highest-scoring drugs obtained from docking studies, which exhibited superior scores with three specific protein targets. To compare the results of the MM-GBSA analysis, a similar screening approach was utilized for approved inhibitors targeting CDK4/6 (abemaciclib) and aromatase (letrozole).
7
Binding Energy Calculation Protocol
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Prime/MM/GBSA module of the Schrodinger was used for calculating relative binding energy of the chosen ligands. XP output file pv.maegz was used for this study. Further, active site of the protein was set for the self-adjustment to itself up to 5 Å for ligand accordingly. The equation for the calculation of Delta G can be sum up as _ Gbind = Ecomplex (minimized) − [Eligand (unbound, minimized) + Ereceptor (unbound, minimized)].
8
MM-GBSA Binding Energy Calculation
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The MM-GBSA approach is frequently used to determine the binding free energy of a chemical compound with a protein or a free ligand. A complicated system’s MM-GBSA can be calculated using the MD simulation trajectory, which is more precise than the majority of scoring functions. Therefore, the Prime MM-GBSA module in the Schrödinger Maestro package was used to apply the MM-GBSA methods in order to calculate the binding free energy (Gbind) of the selected compounds in the complex with the FAK1 protein.
9
Structural Modeling of TLR10-dsRNA Complex
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Open-model (Fig. 2 ) was used for docking of dsRNA which was retrieved from the complex of TLR3-dsRNA (PDB: 3CIY ). The possible interacting residues between RNA and TLR10 were obtained by superimposing the TLR10-ECD dimer to TLR3-ECD dimer. These residues were given as constraints for docking using HDOCK and HADDOCK (Dominguez et al., 2003 (link); Van Zundert et al., 2016 (link); Yan et al., 2017 (link)). The top models for TLR10-dsRNA complex were assessed for compliance of residue constraints. For the top models, binding energy (ΔG) was calculated using Prime-MMGBSA module of Schrodinger. Later the blind dsRNA docking was also carried out using closed-model and open-model without specifying any residues using HDOCK. Such models are referred as “closed-model-dsRNA-blind” and “open-model-dsRNA-blind”. The ECD of docked complexes were protonated at acidic pH (pH = 5.5) using protein preparation wizard module of Schrodinger. The interactions between protein and dsRNA were checked using PLIP (Adasme et al., 2021 (link)) after protein preparation.
10
Ligand Binding Energy Analysis
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MM-GBSA was used to determine the ligand binding energies and ligand strain energies for the top hits in the docking studies. The prime MM-GBSA module of Schrödinger was employed for this purpose. The OPLS3e force field was used with the VSGB solvent model, while the ligands and receptors were taken from the project table and workspace. As the MM-GBSA binding energies are the approximate free energies of binding, a more negative value indicates a stronger binding (reported in kcal/mol).
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