Dr. Sherman works closely with researchers using Schrödinger software for molecular modeling and drug design projects. Here, Dr. Sherman answers some common questions about tools for fragment-based drug design, entropy predictions, and more.
Q: I am interested in computing some entropy terms that I can use to supplement my binding energy calculations. What do you have available?
A: We currently have two scripts on the Script Center to compute entropies. The first one, called rrho_entropy.py,
takes an input poseviewer file and uses the rigid rotor harmonic
oscillator approximation to compute the vibrational, translational, and
rotational entropy loss of the each ligand pose upon binding. The other
script, called pose_entropy.py, is based on the work of A.M. Ruvinsky published in J. Comp. Chem., 26 (11), 2005.
It takes a file with multiple poses per ligand (we recommend 100, as
was done in Ruvinsky's work) and clusters the ligands based on their
RMSD. It then computes the entropy for each cluster and modifies the
docking score to compute the top pose. We are also working on a
conformational entropy script that will be available soon.
Q: I would like to interactively make modifications to a ligand in the Workspace and compute the interaction energy of the modified ligand with the receptor. Is there an easy way to do this?
A: We have a new interface to do this, powered by the script ligand_designer.py. Within the graphical interface, one can move the ligand, retype atoms, add functional groups, and more. A MacroModel
Embrace calculation can then be run on the complex to obtain an
interaction energy. Each calculation populates a viewable table that
stores results, and the desired entries can be exported to the Project
Table.
Q: We have started a new fragment-based discovery project. Do you have any tools to deal with fragments?
A: There are currently three scripts on the Script Center for fragment-based work. The first, called fragment_selector.py, is used to post-process results from a Glide
XP fragment docking calculation. It first applies a ligand efficiency
score to each pose and then selects the top fragment for each region of
the active site based on the ligand efficiency. The next script, called
fragment_molecule.py, takes a set of input molecules and breaks them into fragments based on some simple rules. Finally, fragment_join.py
is used to join fragments based on their proximity and geometry, with
the ability to add up to two methylene linkers if needed. Fragment_join.py can be run after fragment docking calculations or on docked ligand that have been fragmented with fragment_molecule.py.
Q: Is there a way to do flexible superposition of multiple ligands using the tools in the Schrödinger suite?
A: We just developed a new tool called flexAlignMol.py that uses Phase to perform a flexible superposition of multiple ligands on a reference molecule.
Q: I am doing a lot of conformational searches and am finding that I get many conformations, which makes it difficult to analyze. I would like to know if there are any tools that can cluster the results.
A: We have a script called mmod_ligsearch_cluster.py that provides a simple interface to perform a high-quality MacroModel conformation search followed by clustering to reduce the output while preserving a diversity of conformations.
Q: I cannot find a number of scripts on the Script Center that I know used to be there. Where did they go?
A: A number of our scripts have now been integrated into Maestro. The Protein Preparation Wizard is now under the Workflows menu, the Protein Assignment script can be run from the Protein Preparation Wizard, and the Project Table Calculator can now be accessed from under the Table menu of the Project Table. If you notice anything else missing, just let us know and I am sure we can find it.