Small Molecules as Rotamers: Generation and Docking in RosettaLigand
نویسندگان
چکیده
We introduce small molecule rotamers into the rotamer search protocol used in Rosetta to model small molecule flexibility in docking. Rosetta, a premier protein modeling suite, models side chain flexibility using discrete conformations observed in the Protein Data Bank (PDB). We mimic this concept and build small molecule rotamers based on conformations from the Cambridge Structural Database. We evaluate to the small molecule rotamer generation protocol on a test set of 628 conformation,s taken from the PDBBind database, of small molecules with ≤ 6 rotable bonds. Our protocol generates ensembles in which the closest conformation is 0.45 ±0.31Å RMSD from the crystallized conformation. Further, in a set of 21 small molecule protein complexes, 16 of 21 cases a native-like model was in the top 1 % of models by energy.
منابع مشابه
Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand
RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand) making it unfeasible for use in virtual High Throughput Screening (vHTS). To overcome this limitation, we developed a new sampling approach for placing the ...
متن کاملUsing RosettaLigand for Small Molecule Docking into Comparative Models
Computational small molecule docking into comparative models of proteins is widely used to query protein function and in the development of small molecule therapeutics. We benchmark RosettaLigand docking into comparative models for nine proteins built during CASP8 that contain ligands. We supplement the study with 21 additional protein/ligand complexes to cover a wider space of chemotypes. Duri...
متن کاملImproving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand.
Computational protein-ligand docking is of great importance in drug discovery and design. Conformational changes greatly affect the results of protein-ligand docking, especially when water molecules take part in mediating protein ligand interactions or when large conformational changes are observed in the receptor backbone interface. We have developed an improved protocol, SWRosettaLigand, base...
متن کاملBlind docking of pharmaceutically relevant compounds using RosettaLigand.
It is difficult to properly validate algorithms that dock a small molecule ligand into its protein receptor using data from the public domain: the predictions are not blind because the correct binding mode is already known, and public test cases may not be representative of compounds of interest such as drug leads. Here, we use private data from a real drug discovery program to carry out a blin...
متن کاملRosettaLigand docking with full ligand and receptor flexibility.
Computational docking of small-molecule ligands into protein receptors is an important tool for modern drug discovery. Although conformational adjustments are frequently observed between the free and ligand-bound states, the conformational flexibility of the protein is typically ignored in protein-small molecule docking programs. We previously described the program RosettaLigand, which leverage...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2008