Devprev Drug Design Update

Hi everyone,

I want to thank you for taking the time to test the first drug design puzzle. It is very nice to be part of a community that is so enthusiastic and helpful in tracking down bugs, reporting them, and improving science. I know that it can be extremely frustrating testing things that are broken or that do not perform in logical ways. Thank you for sticking it through and reporting the bugs and feature requests.

The idea behind releasing the puzzle to devprev without any information was to get a handle on what needed to be done to improve the drug design module without the constraint of a specific problem being solved. In the future, this will not be the case and a detailed description of the puzzle and the disease you are working on will be given.

This puzzle only featured one small aspect of the drug design tools and modes. In this puzzle, you were allowed to only change the atom identity to a Carbon or Nitrogen. By limiting the tools, we were able to identify specific problems with drug design mode (see below for summary). This is not what the future is of drug design. Adding large and small fragments, extending the small molecule by specific atoms, designing through synthetic rules, and queuing ligands are all tools that were not available. To let everyone get a peek at what is to come, jflat has created another sub group that has all the tools available. We are currently testing this build, but look for a blog post in the future where we will give you instructions on how to obtain it.

Here is a summary of the bugs/features that were reported.

We have tutorials! We just have not released the tutorials. The tutorials take you through a scientific paper where rational drug design was used to create an inhibitor for the FK506 binding protein. The tutorial puzzles will be in the new experimental drug design group that is being set up.

Ligand grids
There were a lot of bugs/features about the ligand grids. A lot of people wanted the color of the grids to be changed. Is it better to have a simple color change is needed or the ability to change the color on the fly is needed?

The ligand grids were put in place to show contact points where you can design acceptors/donors atoms or fragments. Right now, the grids only show acceptors, donors, or repulsive scores. The future of the grids is to include information about structure activity relationships (SAR) of small molecules. SARs help identify regions of the small molecule or protein that like specific features, like hydrophobic/polar atoms, bulky/small fragments, etc. SARs are unique to each protein, so the ligand grids will change.

Finally, there were numerous bugs with the grids. The grids would disappear/appear randomly, or move, or not show when toggled and the slider was moved. These bugs will be fixed!

Ligand jumping out of pocket
I believe that I have tracked down the problem for this. Interestingly, I believe it is how I set up the ligand center filter, which was supposed to keep the ligand in the binding pocket. You have to love irony.

Where to begin? The idea for limiting wiggle, which is what the puzzle was supposed to do, is that drug design is usually done with a fixed backbone with no wiggles/shakes. While this is the general rule of thumb, there are optimization steps done to the backbone and sidechains throughout the design process. The problem with this specific puzzle, and why we wanted to limit wiggle/shake, is that the binding pocket was extracted from a larger protein. There were cutpoints at the end of each helix. Through internal testing, the protein would explode each time I wiggled the protein. I thought that I had fixed the issue, but it looks like there were some problems left.

For the future, the current plan is we will not limit wiggle or shaking. One of the goals of the Foldit community is to develop new strategies to fold proteins. For drug design, we want to keep in alignment with those goals and allow free thought and movement of the protein. New puzzles will not have these constraints associated with them (unless they are really needed).

One thing not shown in this puzzle is on the fly rotamer development. This means, each time you modify the ligand, a whole set of new rotamers are generated. This feature is enabled in the new experimental group.

Scoring is notoriously difficult for small molecule drug design. For this puzzle, we did not make any modifications to the score function to make it easy to distinguish which small molecule was the best. There is a new filter that we have developed that better recapitulates experimental values, but it was not included in the puzzle. Speaking of filters, there will be a whole lot of them introduced in the future!

We look forward to your additional feedback!

( Posted by  free_radical 127 7154  |  Fri, 12/04/2015 - 17:49  |  0 comments )
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