Deleting and redocking ligand

[Mohamadshahir15]

In this project, the main key is to find the binding site of the WDR 91 protein. In order to do this, I have decided to delete the ligand from the 8SHJ and decided to draw the ligand again by using Chemdraw. After converting the file of the ligand to a pdb file, I prepare both protein and ligand for redocking. The protein and ligand bind very well with an exception at the -OH group. This is due to the interaction occurring between the group with Leucine, leading to the bend of the molecule.

The details step-by-step of this experiment is attached on the link here

[mattodd]

Great. In the above, which is the Xstal and which is the docked? Are you able to show the Leu interaction, since I had thought the OH was pointing to solvent, no?

[Mohamadshahir15]

The Blue one is the Xstal and the docked one is in Magenta. Yes, there is a Leu interaction. Should I edit the above issue or add on below on the comment?

[mattodd]

Best not to delete things if you can help it. I would add a new pic below. Looking good already, but good also to see any relevant interactions shown clearly, and we are always interested in any disagreement between experiment and calculation.

[Mohamadshahir15]

As stated from the research paper, the co-crystal structure shown several hydrophobic interaction between Leucine residues (467,477,465) and the ligands. Cysteine (503), Alanine (459) and Leucine (467) formed halogen bond with the ligand. The redock ligand has also shown the same interaction, confirming that we have found the right binding pocket.

In the experimental ligand, there is no interaction from the -OH group with the protein, leading the -OH group to point out to the solvent. However, result from the calculation shows that there is in fact two interactions between the ligand Leucine 486 and Cysteine 487. Leucine formed a conventional hydrogen bond.

[mattodd]

So it looks like the re-docked and original interactions are very similar, i.e. it looks like this re-docking has been successful.

What's perhaps surprising is that the oxetane is not making any interactions with the protein. This moiety seems to be quite important for activity. Is it perhaps merely arranging the rest of the molecule in the right conformation?

In all future docking of other structures, you would expect to see many of these same interactions.

[drc007]

Did you only get a single docked structure? You would normally look at the top 10 scoring structures or so. Also Vina provides a parameter called exhaustiveness to change the amount of computational effort used during a docking experiment. The default exhaustiveness value is 8 ; increasing this to 32 may allow you to identify a more confident result. You may also need to minimise the final pose using the Amber forcefield to get a more refined pose.