Small molecule structures were downloaded from ChEMBL open bioactivity database (https://www.ebi.ac.uk/chembl ) in SMILES format [72 (link)], and converted into 2D structures via the JChem for Excel application (JChem for Office (Excel) 2019.6.0.447, ChemAxon (http://www.chemaxon.com ). Ligand preparation was completed with Schrödinger’s LigPrepmodule (Schrödinger Release 2018-2: LigPrep, Schrödinger, LLC, New York, NY, USA, 2018), structures were optimized with OPLS3e force field (Schrödinger LLC, Release 2018-2, OPLS3e, 2018) [73 (link)], Epik module was used to the generation of various stereochemistry (if undefined) as well as protonation- and tautomeric forms at pH = 7.4 (Schrödinger LLC, Release 2018-2: Epik, 2018) [74 (link)].
Opls3e
Manufactured by Schrödinger
Sourced in United States
OPLS3e is a force field for molecular modeling and simulation developed by Schrödinger. It is designed to accurately represent the physical properties of molecules and their interactions, enabling reliable predictions of molecular behavior.
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5 protocols using opls3e
1
Small Molecule Ligand Preparation
2
Molecular Dynamics Simulations of Biomolecular Systems
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MD simulations in the NPT ensemble were performed for all 11 systems (Table 1 ) by using the Desmond code [30 ,31 ] of the Schrödinger suite and the OPLS3e [38 (link)] force field. The pressure and temperature were kept constant at 1 bar and 300 K respectively, by using the Nosé-Hoover chain and Martyna-Tobias-Klein coupling schemes, respectively [39 (link),40 (link)]. For the numerical integration, the RESPA integrator was employed with a short range/bonded interaction and long-range/non-bonded interactions updated every 2 ps and 6 ps, respectively [41 (link)]. The short-range Coulomb interactions employed a cutoff of 9.0 Å [42 (link)]. The long-range interactions were calculated by using the particle mesh Ewald method with a tolerance of 1 × 10−9. Images were generated by using VMD visualization tools [43 (link)].
3
Molecular Docking of p53 Modulators
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The glide module of the Schrodinger suite was used for all the docking studies using the OPLS3e force field. The grid for docking was generated on the ser46 residue of phospho-mutant p53 in the TAD2 domain. The average structure obtained from the converged simulation of phosphor deficient p53/p62 complex was used as the target protein for docking. The grid file was further used to dock Cucurbitacin-B, Wi-A, Wi-N, CAPE, and ARC ligands using glide extra precision flexible docking (Friesner et al., 2006 (link)). For p53 mortalin abrogation, the grid generated for p53 were along the residues Tyr327, Gln331 and Arg333. The interacting residue Glu263 has been taken as the central residue for generating the grid for Mortalin.
4
Molecular Dynamics Simulations of Protein
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For Molecular Dynamics (MD) simulations the Desmond program (Schrödinger, LLC) and OPLS3e (Harder et al., 2016) force field was used , with a simulation time set to 1000 ns for monomer and 200ns for dimer. For the simulations temperature was 300 K, pressure was 1.0325 bar, while cut off radius was set to 10 Å. The whole system was considered as isothermal-isobaric (NPT) ensemble class. TIP3P model (Berendsen et al., 1981) was used for modelling of the solvent. MD system consisted of one molecule of the protein placed into the cubic box. Input and output files in the case used were prepared on protein preparation wizard (Madhavi Sastry et al., 2013) , analyzed and visualized with Maestro (Schrödinger, LLC) graphical user interface (GUI).
5
Protein-Ligand Docking Workflow
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The core proteins were identified from the construction and analysis of the protein interaction networks using the Protein Data Bank (http://www.rcsb.org/), and their 3D structures were saved as files in the Protein Data Bank format. The PubChem database (https://pubchem.ncbi.nlm.nih.gov/) was used to search for the key compounds, and their 2D structures were downloaded. The proteins and small molecules that were identified were subsequently imported into Schrödinger molecular docking software; protein receptors were prepared using the Protein Preparation Wizard module. All water molecules located >5 Å away from the active site were removed and incomplete amino acid residues were supplemented, het states were generated using Epik at pH = 7.0 ± 2.0. Hydrogen bonds were assigned via PROPKA at pH = 7.0. Energy was minimized using an OPLS3e force field until the relative mean SD between the minimized structure and the crystal structure exceeded 0.30 Å, and ultimately used as a receptor for molecular docking. Small molecule ligands were prepared using the LigPrep module (Schrödinger, Inc. New York City). The compounds were ionized and desalted at neutral pH 7 ± 2.0 with Epik, and energy was minimized using OPLS3e (Schrödinger, Inc. New York City).
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