Ligand Preparation for Glide

To give the best results, the structures that are docked must be good representations of the actual ligand structures as they would appear in a protein-ligand complex. This means that the structures supplied to Glide must meet the following conditions:

1. They must be three-dimensional (3D).
2. They must have realistic bond lengths and bond angles.

Glide only modifies the torsional internal coordinates of the ligand during docking, so the rest of the geometric parameters must be optimized beforehand.

3. They must each consist of a single molecule that has no covalent bonds to the receptor, with no accompanying fragments, such as counter ions and solvent molecules.
4. They must have all their hydrogens (filled valences).
5. They must have an appropriate protonation state for physiological pH values (around 7).

For example, carboxylic acids should be deprotonated and aliphatic amines should be protonated. Otherwise a neutral aliphatic amine could improperly act as a hydrogen-bond acceptor in the docking calculations, or could occupy a hydrophobic region without incurring the large desolvation penalty that XP Glide docking would have assessed if the amine had been properly protonated.

Protonation states are particularly crucial when the receptor site is a metalloprotein such as thermolysin or a MMP. If the metal center and its directly coordinated protein residues have a net charge, Glide assigns a special stability to ligands in which anions or polar groups coordinate to the metal center.

6. They must be supplied in Maestro, SD, Mol2, or PDB format, or as SMILES strings.

Maestro transparently converts SD, Mol2, PDB, and other formats to Maestro format during structure import. SMILES strings are converted to 3D and prepared with LigPrep. However, Glide has no direct support for other formats, so you should ensure that 3D structures are provided in Maestro, SD, Mol2, or PDB format before starting Glide jobs.

All of the above conditions can be met by using LigPrep to prepare the structures. See the LigPrep Panel topic for more information.