fragmentor Lv 1
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.
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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!
