Foldit Drug Design Part Two

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Hi folks!

My name is Sandeep Kothiwale (aka fragmentor). I am continuing the Foldit drug design blog this week. I am a graduate student at Vanderbilt University and developing the drug design module of Foldit. This blog describes the shake/wiggle feature for small molecules which is analogous to the one for protein molecule.

Drug molecules (small molecules) bind to a target molecule (protein in our case) and effect the function of the protein. This change in protein function leads to the desired physiological effect of relieving disease or its symptoms. For example, Imatinib (Gleevec) binds and blocks an enzyme whose over-activity causes leukemia.

As with imatinib, all drug molecules bind their targets in a specific pocket in a particular 3D arrangement. For successful drug design, one needs to recapitulate the expected binding pose of the putative drug (ligand) to the protein. This requires that 3D structure of ligand be determined which is able to bind the target. Spatial arrangement that atoms in a molecule can adopt with respect to each other is called a conformation. A molecule can adopt multiple freely convertible conformations by rotations about individual single bonds. Thus enumeration of 3D conformations is essential in modeling ligand binding in Foldit. As you might know, we use the wiggle feature for enumerating side-chain conformations. This is accomplished using a set of rules that have been identified for 20 or so amino acids from known protein structures in the Protein Data Bank (PDB). As you can imagine enumeration of small molecule conformation is substantially more complex than wiggle for 20 or so amino acid side chains because of large chemical space.

Foldit will use an algorithm that I helped develop for sampling conformations of ligands. It uses information contained in the Cambridge Structure Database (CSD), a repository of small molecule crystal structures (on a side note, the CSD group has let us use their database free of charge!). The algorithm uses a CSD-derived database, the csd-rotamer library that contains statistics about most commonly seen conformations of small molecular fragments. Given a molecule of interest, the algorithm determines which smaller fragments are part of it and uses information in the csd-rotamer library to sample conformations.

During the drug-design process ligand will be built by adding fragments to the base fragments. One could hit the ligand-wiggle button to sample conformations of ligands and let Rosetta (Foldit’s engine) choose the conformation that best fits the binding pocket. We have a video of this cool technology above (and at the link). The video first shows adding a fragment to the base small molecule (shown in orange) and then at 26s, the new fragment rotates. We are using HIV protease as a test case. Check it out!

( Posted by fragmentor 83 2645  |  Mon, 02/02/2015 - 18:14  |  4 comments )
2
Joined: 09/19/2011
Foldit Drug Design

This all looks very interesting! I'm looking forward to trying the new tools. Do you have any idea when the new tools will be released to us to try?

Joined: 01/12/2015
Groups: None
I personally play video

I personally play video games, and I am about to say something that drives me me nuts when I hear it, but the drug design stuff will be ready in the near future. We are not working on a specific timeline, but I think its safe to say that at least some of the features will start to creep into Foldit soon. We had a meeting yesterday where we came up with specific action items to accomplish before we release some content. When we get those things done, we will announce it and have a new puzzle up!

-free_radical

egran48's picture
User offline. Last seen 1 year 7 weeks ago. Offline
Joined: 03/31/2014
Groups: Go Science
Drug design

Thank you for the excellent video and explanation of how it works. I am still gaining experience in Foldit and always ready to try new tools.Via this blog, we can see that Foldit really value the players, thanks.

Joined: 05/19/2009
Groups: Contenders
I cannot see the ligand.

Hi, thank you for giving us an update. I can barely see the ligand. It would be good to switch off all unnecessary graphics (voids to begin with, and then sidechains) to show the ligand, then see how something gets added and then how it apparently moves because I cannot see any of that right now. I did watch the video several times.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
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