Chirality Manipulations Using Maestro and LigPrep

Both Maestro and LigPrep have the ability to manipulate the stereogenic composition of a three-dimensional molecular structure. Maestro includes graphical features that can exchange the chirality of one or more centers, as well as easily generate the enantiomer of a displayed structure. Correspondingly, a LigPrep preparation has the ability to sample some or all of the chiral centers in one or multiple input structures. Finally, the combination of the Project Table and LigPrep enables the expansion or inversion of selected subsets of chiral centers in one or more structures easily and quickly.

In the Workspace, you can perform inversions as follows:

  • To invert a single chiral center, right-click on the center and choose Additional Edits → Invert Chirality.

  • To invert several chiral centers, select the centers, then right-click on one of the centers and choose Additional Edits → Invert Chirality.

  • To invert all centers (producing the enantiomer), select the entire molecule, then right-click on an atom and choose Additional Edits → Invert Chirality.

These operations can only be performed on chiral atoms that are not a part of a ring system. To invert the chirality of an individual ring system atom, use LigPrep as described below.

In addition to Maestro’s built-in graphical tools, which modify individual chiral centers and produce enantiomers, LigPrep can also generate and sample alternative chiralities on a broader scale. Generally, in addition to 2D to 3D conversion, LigPrep can sample and expand ionization states, tautomers, ring conformations, and alternative chiralities. For the latter, both Maestro-formatted files and SD-formatted files have the internal ability to indicate the specified chirality at some or all stereogenic centers, usually "R" or "S". LigPrep and the Stereoizer have three basic usage modes that utilize this information:

  • Retain specified chiralities—For structures with specified chirality information, LigPrep attempts to generate output structures that match the chirality indications at all such stereogenic centers. LigPrep tries to match the specification whether or not the input 3D geometry about the chiral centre (if any) matches this specification. All unspecified chiral centers in the structure are expanded.

  • Determine chiralities from 3D structure—Specified chiralities are ignored, and no alternative chiralities are generated unless the chirality cannot be determined from the structure (as is the case for 2D structures). Output structures have the same stereogenic makeup as the input, and all chiral centers have their specification changed to match the input structure.

  • Generate all combinations—The input specifications are ignored, and and geometrically feasible stereoisomers (up to the maximum number requested) are generated.

If the chirality specifications were not included in the original structure file, or the molecule was constructed in Maestro, the specifications can be easily assigned by simply running LigPrep with the Stereoizer set to Determine chiralities from 3D structure. You may select to turn off the Ionizer, Tautomerizer, and Desalter if you prefer no additional expansion when only specifying chiralities. After incorporation, the chirality specifications are listed in the Project Table.

Once the chirality specifications are listed in the Project Table for the structures of interest, the combination of the Project Table and LigPrep provide a simple, easy method to invert or sample a subset of chiral centers in one or more structures.

To invert a chiral center using LigPrep, simply adjust the specification in the appropriate property cell for the structure of interest to the other "R" or "S" indication, for instance from 9_R_8_13_10_37 to 9_S_8_13_10_37. You may want to duplicate the entry in the Project Table prior to adjusting the designation. Using the modified entry in a subsequent LigPrep computation with the Retain specified chiralities mode, generates the requested chirality change. The user can make changes to multiple structures by modifying any of the specified chiralities, selecting all of the modified structures in the Project Table, and running the LigPrep preparation with Use structures from set to Selected entries.

In contrast, to sample or expand alternate chiralities once the chiral centers are specified, simply delete or remove the specification from the Project Table cell. A subsequent LigPrep preparation, using the Retain specified chiralities mode, maintains the other, indicated chiralities, but expands the chiralities of the centers with specifications removed. Multiple structures can be expanded in this way using selected entries as the input.