The molecular interactions between compounds 8 and 9 and tubulin were investigated. Molecular docking was performed using the tubulin crystal structure (PDB: 4O2B), and Maestro Schroödinger software (Schrödinger Release 2021-4) as previously described [56 (link)]. The ligands were prepared using the LigPrep tool (LigPrep, Schrödinger, LLC, New York, NY, USA, 2021), and the protein was minimized and optimized using the Protein Preparation Wizard (Protein Preparation Wizard; Epik, Schrödinger, LLC, New York, NY, USA, 2021). After grid generation, the derivatives were docked into the colchicine-binding site, and post-docking analysis was performed for the docked compounds using the Glide tool (Glide, Schrödinger, LLC, New York, NY, USA, 2021). Moreover, the binding free energy calculations were conducted for the docked complexes using Prime MM-GBSA, VSGB as the solvation model, and an OPLS4 force field.
Ligprep tool
Manufactured by Schrödinger
Sourced in United States
LigPrep is a computational tool for the preparation of ligand structures. It performs a variety of operations on input molecular structures, including the addition of hydrogen atoms, the generation of tautomers and ionization states, and the conversion of 2D to 3D structures.
Automatically generated - may contain errors
Lab products found in correlation
Protein preparation wizard, by Schrödinger (4 mentions)
Glide tool, by Schrödinger (3 mentions)
Ligprep, by Schrödinger (2 mentions)
Small molecule drug discovery suite, by Schrödinger (2 mentions)
Molecular modeling suite 2019, by Schrödinger (1 mentions)
Piperine, by Merck Group (1 mentions)
Maestro 2020 4, by Schrödinger (1 mentions)
Glide 6.9 module, by Schrödinger (1 mentions)
Maestro graphical user interface, by Schrödinger (1 mentions)
L1400, by Selleck Chemicals (1 mentions)
Epik tool, by Schrödinger (1 mentions)
Chemdraw 18, by PerkinElmer (1 mentions)
Maestro tool, by Schrödinger (1 mentions)
Sitemap, by Schrödinger (1 mentions)
Epik module, by Schrödinger (1 mentions)
40 protocols using ligprep tool
1
Molecular Docking of Tubulin Inhibitors
2
Ligand Preparation for Virtual Screening
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Prior to virtual screening, our Medicinal and Biological Chemistry (MBC) library20 (link) was prepared using the LigPrep tool from the Schrödinger software package. LigPrep allows ligand preparation by adding hydrogen atoms, neutralising charged groups and generating the different ionisation states and possible tautomers followed by energy minimisation using the same force field previously used for protein preparation. All compounds were prepared at physiological pH conditions (pH 7.5).
3
Phytocompound Structural Preparation
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The 3-dimensional structures of the phytocompounds considered as ligands were retrieved and downloaded (Fig. 4 a–h) as mol files from the site of Pub Chem. The molecules were processed using the LigPrep tool from Schrodinger to obtain the perfect conformation by the addition or removal of hydrogen atoms with respect to the OPLS_2005 force field.
4
Ligand Preparation for Structural Analysis
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The ligands WA, TAM and CAP were obtained from the PubChem database (https://www.pubchem.ncbi.nlm.nih.gov/ ) [25 (link)] with the respective PubChem IDs 265237, 2733525 and 60953 in SDF format. These ligand structures were subsequently stabilized and meticulously prepared using the LigPrep tool of the Schrodinger suite 2023-2. Here, the diverse ionization states, stereoisomers and tautomers of the ligands were achieved. The ligands were prepared for their three-dimensional (3D) coordinates by the addition of hydrogen, energy minimization and enabling a proper force field [41 , 43 (link), 44 (link)].
5
Tau-Vinblastine Interaction Modeling
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Based on literature review, tau competes with vinblastine during microtubule interaction which needed further introspection from in-silico perspective 21 (link)–23 (link). For the same reason, β-α subunits, PT-β-α subunits and HPT-β-α subunits were considered for docking with vinblastine obtained from Protein Data Bank (PDB id: 4EB6) 54 (link) using Glide tool of Schrodinger suite 55 (link). Lig-Prep tool of Schrodinger was used to generate 28 conformers of vinblastine based on protonation states at pH=7.0+/−2.0 using Epik. The docking site on the tubulin protein within the complexes was generated using receptor-grid generation protocol of Glide by selecting the residues which are α tubulin: 240–252;327–341; 348–353 and β tubulin: 212–215; 172–181; 215–223 22 (link). A scaling factor of 1.0Å was set to van der Waals (VDW) radii for the atoms of residues that probably interact with ligands with the partial atomic charge cutoff of 0.25Å. The scaling factor of van der Waals radii for ligand was set to 0.80 Å and partial charge cut-off of 0.15A. An extra precision (XP) mode of Glide docking was done which does extensive sampling and provides reasonable binding poses. Post-docking, the minimization of docked complexes, was carried out to obtain the glide score.
6
Comparative Docking of Coumarin Compounds
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Compounds 23 and 70 were prepared in the open and closed
coumarin forms using the LigPrep tool of Schrödinger and minimized
with the OPLS4 force field. Subsequently, both stereoisomers were
docked into the active sites of hCA IX and hCA XII using the Glide
tool of Schrödinger with the XP settings. The three highest-scoring
poses were obtained for each ligand, and the poses were subsequently
minimized using the Prime tool and MM–GBSA forcefield. To this
end, the ligand and all residues within 4 Å were unrestrained,
except the zinc ion and zinc-binding residues.
coumarin forms using the LigPrep tool of Schrödinger and minimized
with the OPLS4 force field. Subsequently, both stereoisomers were
docked into the active sites of hCA IX and hCA XII using the Glide
tool of Schrödinger with the XP settings. The three highest-scoring
poses were obtained for each ligand, and the poses were subsequently
minimized using the Prime tool and MM–GBSA forcefield. To this
end, the ligand and all residues within 4 Å were unrestrained,
except the zinc ion and zinc-binding residues.
7
Screening FDA-approved Drugs for Novel Ligands
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The structure of the approved drug was retrieved from the database and a structure search was performed. In this study, we screened FDA approved drug library as a potential source for ligand screening. The drug was downloaded and analyzed for 3D conformations into the drug discovery platform. The selected FDA-approved drugs were screened. The ligands were validated and prepared for docking using the LigPrep tool within the Schrodinger software suite. The screened ligands were further optimized to OPLS3e forcefield within all possible states generated at pH pH 7.0 ± 2.0 using Epik. The selected combinations with stereoisomers and tautomers were generated. The specified chirality was further retained and ligands were generated using OPLS3 force field in water using the Powell - Reeves conjugate gradient method with 2500 steps and the convergence threshold was 0.05.
8
Quercetin and Caffeic Acid Docking
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Structures of quercetin and caffeic acid were acquired from PubChem in SDF format, while the ligands were prepared for docking calculations utilizing the LigPrep tool within the Schrödinger Software program (version 11.5). The ligands were prepared with the OPLS3 force field, and considering ionization states (pH 7.0 ± 2.0), 32 stereoisomers were generated for each compound (Aboul-Soud et al., 2022 (link)).
9
Molecular Docking of AChE, BACE-1, and Aβ
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Molecular docking
studies were performed by using the Schrödinger software package
(Schrödinger Release 2015-4: Maestro, version 10.0, Schrödinger,
LLC). The 3D crystal coordinates of AChE, BACE-1, and Aβ were
retrieved from the protein data bank (www.rcsb.org ) with pdb IDs 1EVE, 4B05 , and 1IYT , respectively. The proteins were preprocessed,
polar hydrogens were added, and water molecules were removed. Taking
into account the drug solubility and permeability, the heteroatoms
were ionized at biological pH. To reduce steric clashes by amino acids,
hydrogen bonds were optimized. Using the Ligprep tool of Schrödinger,
ligands were prepared, which adapt a 3D structure. Prior to docking,
a cubic grid dimension with various dimensions with the grid points
along the x, y, and z axes was generated with a van der Waals radius of 1. The ligands
were then docked into the generated grids, and the interactions of
the prepared ligand with the receptor were calculated using the XP
ligand docking in glide. Interactions between ligands and enzymes
were analyzed, and hydrogen atoms that are nonpolar were merged to
carbon atoms. The docking procedure was validated by docking the cocrystallized
ligands of AChE and BACE-1 in the respective enzymes, and RMSD was
calculated.
studies were performed by using the Schrödinger software package
(Schrödinger Release 2015-4: Maestro, version 10.0, Schrödinger,
LLC). The 3D crystal coordinates of AChE, BACE-1, and Aβ were
retrieved from the protein data bank (
polar hydrogens were added, and water molecules were removed. Taking
into account the drug solubility and permeability, the heteroatoms
were ionized at biological pH. To reduce steric clashes by amino acids,
hydrogen bonds were optimized. Using the Ligprep tool of Schrödinger,
ligands were prepared, which adapt a 3D structure. Prior to docking,
a cubic grid dimension with various dimensions with the grid points
along the x, y, and z axes was generated with a van der Waals radius of 1. The ligands
were then docked into the generated grids, and the interactions of
the prepared ligand with the receptor were calculated using the XP
ligand docking in glide. Interactions between ligands and enzymes
were analyzed, and hydrogen atoms that are nonpolar were merged to
carbon atoms. The docking procedure was validated by docking the cocrystallized
ligands of AChE and BACE-1 in the respective enzymes, and RMSD was
calculated.
10
Docking Analysis of Gefitinib Off-Targets
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The potential off-targets-identified from MIF similarity search were further processed for binding analysis of gefitinib and previously characterized respective ligands. The Glide 6.9 ligand-receptor docking program (Schrödinger 10.4; Schrödinger Inc, USA) was used for docking of gefitinib to each off-target structure. The ligand library of gefitinib was prepared by LigPrep tool from Schrödinger program with OPLS-2005 force field. Receptor grid was generated in the vicinity of bound ligand of each identified-off target crystal structure using Glide-Receptor Grid generation tool with default parameters. Ligand docking was performed with extra precision (XP) Glide docking module. The binding energies of docking poses were calculated using MM-GBSA method (Prime, Schrödinger Inc, USA) with default parameters.
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