No, it is not. But one can imagine a workaround. For example, a compound library can be screened first against an empty pocket. Then, new pockets, featuring the docked top hits from the first screen, could be used to screen the library again.

However, my major concern is not a technical solution, but the rationale. Why on earth one would need to do that? No one would want to develop a drug consisting of two molecules simultaneously binding to the same protein site.

Yes and no. Functionally, it *could* be done. At the end of the day, all docking is is a set of atomic coordinates stored in an algorithm, and you already have two molecules, and many algorithms already allow you to independently choose protein residues to be flexible, sort of like adding extra molecules to the mix. But I am not aware of any software that will do two molecules other than the receptor without modifying the source code. If you're really set on doing it, the best option would probably be MOE - use the SVL to construct your own docking algorithm that examines two molecules simultaneously.

Alternately, you might look at a molecular dynamics simulation. It's much less user friendly, and much more computationally intensive, but it's also meant to include as many molecules as you want in the same simulation.

It may not be rational from drug development point of view. However, in some special cases it might be useful. For example, if the binding stoichiometry of a ligand is more than 1, one maybe interested in docking multiple copies of the same ligand on the same protein. However, it may not be necessary, in such a case, to actually dock more than one ligand. Instead, one can do blind docking and find out the n possible binding sites on the protein. Another situation could be when someone wants to model the "initial guess" (for MD simulation) of, say, how the substrate approaches when an inhibitor is bound, to study competitive binding/steric hindrance etc. of an inhibitor. Then, one can just sequentially dock the molecules.

Yes it is possible. It is not preferable in drug design studies but in some point it may be needed for SAR studies in uncompetitive inhibition type.

Hi,

Huameng Li and Chenglong Li have done multiple ligand docking:

The method is called Multiple Ligand Simultaneous Docking (MLSD). This algorithm was implemented on AutoDock, I don't know if it still can be downloaded.

@ Dmitri Kireev

Sir, In case of resistance of drug molecule and if one of known site of protein is blocked due to resistance then with the same protein we can dock the newer molecules, is it possible sir?