Docking despair

I work on a number of drug design projects where the number of compounds being produced by the chemists is far greater than I could possibly hope to co-crystallise with the protein and solve the subsequent structures. My hope was that I could use a docking program to quickly get an idea of how compounds might bind which could perhaps help me decide which compounds are interesting enough to put into crystal screens. I have three completely separate projects, and libraries of compounds for all three projects where I know both the experimental binding affinity and structure. Thus I figured the best thing to do was to run these libraries through a number of docking programs and see which predicted my binding conformations best. I have no hope of predicting affinity data because docking algorithms are not up to this yet, but a hint at the order of affinities would be an extra bonus. If this all worked successfully I would then try looking at libraries such as ZINC to try and find totally new compounds.

After about a year, and a couple expensive software licenses, I have come to the conclusion that no current docking programs will be able to help me at this point in time. I have evaluated GOLD, FlexX and Autodock 4 with libraries from all three projects, played around with lots of parameters, and it seems none of these programs can accurately predict binding orientations, and certainly cannot rank compounds in any experimentally meaningful way. Meanwhile the couple ZINC sub-libraries I did look at with both Autodock and FlexX did not manage to dock many compounds in a meaningful way.

I think the reason for this failure is down to the protein structures themselves. Looking at the literature and at the situations where docking has worked well for people, it seems that proteins with very well defined binding sites and obvious hydrogen bond donors/acceptors work well with docking prgrams. Although two of my proteins contain strongly charged positive ions, the rest of the binding pockets rely on hydrophobic interactions which seem to be difficult to model (and hence recognise) by the docking programs. Meanwhile my third protein is a promiscuous aromatic binder whose binding site is necessarily quite unspecific, something that again is probably not good for the success of the docking programs. Thus I think at the moment the docking programs are not yet able to model my systems, and cannot really help with quickly screening my compounds.

However I do have some ideas for using the programs to simulate molecular dynamics...

Autodock email list

As a structural biologist I am used to the excellent ccp4 email list populated by the best crystallographers in the world. It is sometimes rather intimidating to post a question, however you always know that you will get an excellent answer...

...and then you have the autodock email list... oh dear...

Although there are one or two people who seem to be genuine scientists, the rest of the posts seem to be written by clueless students just looking to take short-cuts on their projects. I presume that because autodock is free software various teachers around the globe have set assignments using it, however the result seems to be an inundation with stupid questions written in text speak. This is a real shame because molecular docking is a potentially exciting technology which could well benefit from the type of discussions held on the ccp4 email list. I suppose I should just give up on the list, however every now and again something interesting gets written. Perhaps the guys at scripps should think about moderating the list in order to improve the quality?

Have been looking at doing some dockings with a protein containing some calcium atoms. A couple years ago I had problems doing this in Autodock, however after speaking so the guys on the autodocking bulletin board I have found the following:

As far as I can gather the current situation is that ADT now recognises the calcium atom so long as it is labeled in the normal way in the pdb file and automatically assigns Rij and Rii from the AD4_parameters.dat file, HOWEVER does not assign a charge to the atom which you have to do manually by editing the pdbqt file.

This then raises the question what the charge on the calcium atom should be? A couple years ago Garrett suggested using the formal charge of 2+, however I am not certain this is strictly correct. In my case the calcium atom is coordinated by six protein ligands and the small molecule I am trying to dock in the classic calcium pentagonal bipyrimidal geometry. Given the proximity of six oxygens surely the apparent charge on the calcium that the small molecule is seeing will be substantially less than +2? Furthermore surely the presence of such a highly charged atom will affect the charge on these residues and thus alter the electrostatics of the binding site? Wouldn't it be far more accurate for the charge calculation to take into account the presence of the calcium atom (and presumably also the pH)? It feels like a bit of a fudge to manually edit the pdbqt file to the approximate value.

Incidentally I have compared dockings with the calcium charge set to +2 and 2/7. At +2 the electrostatics completely dominate the binding whilst at 2/7 the ligand is never in the correct orientation (as compared to my 1.8A X-ray structure).