Structure Preparation for DivCon
Easily characterize and optimize structures to streamline your drug discovery workflow
The quality of your structures significantly impacts the success of your CADD campaigns. To address the “garbage in/garbage out” paradigm you need CADD software capable of accurate protonation state determination, tautomer enumeration, structure optimization and characterization.
- Use your graphical user interface (GUI) of choice—we usually use MOE platform, but you can also use other tools, such as Maestro.
- Efficiently perform rigid-receptor docking and induced-fit docking refinement protocols with properly prepared structures.
- Maximize the success of CADD and SBDD by using QM/MM coupled with our integrated support X-ray or Cryo-EM density
- Send your structures to us and we’ll prepare them for you—we can work with PDB, mol2, and SDF files and quickly get your structures back to you.
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Follow These Standard Preparation Steps
If you are using MovableType (MT), QM, QM/MM (ONIOM), or the DivCon Plugin (PHENIX/DivCon or BUSTER/DivCon), you should be sure the structure is fully prepared prior to proceeding.
Evaluate the overall quality of your structural model and explicit water molecules. Evaluate the overall quality of your structural model and explicit water molecules.
Add protons, and add them carefully. MOE includes the Protonate3D tool, which helps visualize and double check proton placement. Otherwise, use the –prepare command line argument in qmechanic to add protons.
Structure Minimization or refinement
Minimize added atoms, such as protons, waters, rotomers, with the ligand in the active site.
Dock ligands using either MTDock, the included SVL script in MOE/batch, or the MOE Docking Panel. Include only docking poses which you feel accurately represent the potential binding modes of the structure. These initial landscape minima are critical to MTScoreE, and they are likewise important when you perform subsequent QM/MM or crystallographic refinement.
Run the Movabletype Ensemble Scoring (MTScoreE) to rank binding modes.
Generally, inputs for MovableType include prepared PDB and/or mol2 files for the target and ligand. You can also use SDF files throughout the virtual screening workflow to communicate docked poses or conformers as needed.
Properly Scale Your Structures for MovableType
As with any modeling or simulation method, you’ll likely need to scale your final results to produce ∆G values with low absolute errors. Some scaling should be performed in your own work based on a set of known parameters.
Generally, scaling does not impact correlation but it does impact total error (such as mean unsigned error or MUE or RMSE). By default, all values produced by MovableType Ensemble and End State scores are scaled based on our treatment of 795 chosen PDBBind structures, and most of our reported results are based upon this default scaling.
However, as you gain a better understanding of the structures within your project, consider using a Leave One Out (LOO) or other analogous process.