free_radical Lv 1
Welcome to the first of an ongoing series of drug design puzzles!
Your first puzzle will be to determine which combinations of C and N will make the ligand bind better in the protein pocket. To assist you, we have provided two new tools and two new filters. The goal of this very first puzzle is two-fold, scientific and feedback.
Scientific goal
Can you determine which single atom substitution results in better binding affinity of the drug into the binding pocket? We have given this same problem to medicinal chemists and we have their results. Can you beat them?
Feedback goal
What do you like about this puzzle? What do you not like? Are the tools and filters useful? What do you want to see? What can we do to make you more successful?
New filters
DDG Score Filter
This filter correlates with experimental values and is used often in ligand docking and ligand design problems by Rosetta scientists. The filter is calculated by taking the total score of the complex (protein and ligand) and subtracting the complex with the ligand removed.
Ligand Center Filter
This filter is to show you where the ligand should be in the binding pocket. Because drug design occurs in binding pockets, and in this case we know exactly where the drug binds, you will be penalized if you move the ligand outside of the binding pocket by the filter.
New tools
Ligand Design Tool
The Ligand Design tool allows you to add, delete, and modify atoms in a small molecule. For now, we have only allowed the substitution of carbon (C) to nitrogen (N) and vice versa, but many more of the tool’s features will be unlocked as future puzzles are released. In order to modify a small molecule’s atom, all you have to do is click the “Ligand Design” mode, click on the atom of a small molecule that you want to change, and then click on either “C” or “N” to substitute for that atom. It’s a remarkably simple, but powerful tool to utilize in the drug design puzzles.
Ligand View Tool
This tool works by clicking on it and then the ligand. A series of new viewing options will be available. The hydrogen bond acceptor and donor options allow you to view where the acceptor and donor are on the backbone and sidechain. The repulsive grids show you where you will get a bad score if you have atoms in that location. Finally, the ligand isosurface helps outline the binding pocket.
Tips
Drug design requires you to know what elements are the atoms in the ligand. To turn on atom coloring follow these steps:
menu -> general options -> click show advanced GUI
click view menu -> color: -> Score/Hydro + CPK
Although you can change any atom in the ligand, there is only experimental data on 3 positions on the ligand (See image below, marked by X in the 2D picture and arrows in 3D). We have data for any combination of N and C at those three positions.
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Enjoy, and please post your feedback and questions here for us.