V10.5 of ForgeTM, the powerful computational chemistry suite for understanding structure activity relationship (SAR) and design, is now available. This release introduces significant enhancements to molecule alignment, plus the new Conformation Explorer, to visualize and inspect conformational populations. Also included are a large number of GUI styling and usability improvements.
Improved molecule alignment
Molecule alignment is the core experiment in Forge. It is key to developing robust qualitative or quantitative SAR models, building FieldTemplater pharmacophore hypotheses, understanding the design of new compounds and small scale virtual screening experiments (for larger scale virtual screening use Blaze). V10.5 enables fine-tuning of alignment results by introducing appropriate constraints, an optimized substructure alignment algorithm, and new similarity scoring options.
Field and pharmacophore constraints
Field and pharmacophore constraints bias the alignment algorithm by introducing a penalty which down-scores results that do not satisfy the constraint. This provides you with a mechanism for ensuring that the results that you get from your alignment experiment fit with the known SAR or with your expectations.
With field constraints, you can specify that a particular type of field must be present in the aligned molecule. For example, you may want to a constrain a positive field where you want an interaction but this can be matched by both H-bond donors and other electropositive features such as the aromatic hydrogens in the example below.
V10.5 introduces the new pharmacophore constraints, which ensures that your desired pharmacophore features (e.g., Donor H, Acceptor, Cation, Anion) are matched by an atom of a similar type in the alignment results. A pharmacophore constraint can be used when you are certain that a particular interaction requires transfer of electrons (as in H-bonding or metal binding) in addition to the electrostatic character of the interaction.
Pharmacophore constraints introduce a tighter constraint on the alignment than a field constraint. Where field constraints allow matches across chemical features, pharmacophore constraints are limited to matching specific functional groups (e.g., specific donor-acceptor interactions): alignments that do not place a suitable atom on top or close to the constrained atom cause a penalty to be applied to the score. However, pharmacophore constraints in Forge V10.5 go beyond traditional H-bond donor/acceptor definitions to include, for example, covalent centres and metal binding motifs giving the ability to ensure that key warheads always align in the correct positions.
While field and pharmacophoric constraints are a powerful way of fine tuning alignment results, we recommend that they are using sparingly, as they will be introducing a bias in your Forge experiment. E.g., introducing a pharmacophore constraint on the indazole NH of the PDB 4Z3V ligand in Figure 1 – left would not have matched the aromatic hydrogens of the active ligand in Figure 1 – right.
Figure 1. Left: Ligand from PDB: 4Z3V with pharmacophore and field constraints. Right: Active BTK ligand which satisfies both constraints.
Improved alignment and scoring
Enhancements to alignment and scoring, accessed from the advance options panel, include:
- Option to require full ring matches, and to bias the alignment towards a specific substructure specified by a SMARTS pattern, in the maximum common substructure alignment algorithm
- New functionality to weigh specific fields independently when scoring
- New similarity metrics to provide alternate scoring methods for the alignments
- New widget for adding field and pharmacophore constraints.
New Conformation Explorer
Molecular conformations are central to Forge. The conformation hunter does a good job of generating a diverse range of energetically accessible conformations. V10.5 gives you the opportunity to more easily inspect the conformations generated for your molecules, enabling you to interact with and edit the populations.
In the new Conformation Explorer, you can inspect a set of conformations with respect to energies, measured distances/angles/torsions, as well as calculate the CSD torsion frequency for each rotatable bond to assess the feasibility of the generated conformations.
Conformations are listed in order of increasing relative conformational energy. Unrealistic conformations or those which are not deemed interesting can be selected and removed from the conformation population for that molecule. Preferred conformations can be promoted to the reference role in Forge with the click of a button.
CSD torsion frequencies can be calculated for all rotatable bonds. These are based on the Torsion Library which contains hundreds of rules for small molecule conformations derived from the Cambridge Structural Database (CSD) and curated by molecular design experts. CSD torsion frequencies are useful to highlight cases where the torsion angle in a calculated conformation is not one that is frequently observed in the CSD, and accordingly is a possible cause for concern.
Distances, angles and torsions can be measured for each conformation and those values can be used for filtering or generating a histogram plot.
Conformation energies can also be plotted in an interactive histogram plot. In Figure 2, the column or bucket with the blue highlight reflects the current conformations shown in the 3D view; the grey columns or buckets reflect to conformations which do not pass the set of filters.
Conformations can be filtered by energy, CSD torsion frequency and calculated distances, angles, torsions. Smart coloring includes coloring by energy and by CSD torsion frequency.
Figure 2. The Conformation Explorer in Forge. Rotatable bonds are colored and labelled by CSD torsion frequency.
Other new features and improvements
This V10.5 release also includes a variety of additional new functionalities and improvements to the Forge interface, including:
- Enhanced Molecule Editor with a more intuitive layout, featuring a radial plot that is updated as changes are made to a molecule and the new ‘Save a copy’ button to store your molecule directly into the project without leaving the editor
- New support for touch screen displays
- Enhanced stereo view functionality with improved accessibility
- New functionality to export Activity Atlas™ models as surfaces from the GUI
- New Forge surface command-line binary to export Cresset field surfaces (positive, negative, hydrophobic and vdW)
- New functionality to sort disparity matrixes in Activity Miner™ by Forge project tags, enabling easier identification of molecules of interest
- New capability to export molecules by drag-and-drop to the Windows desktop (Windows only)
- New capability to annotate and re-name Storyboard scenes
- New tagging of project molecules from the 3D window and according to cluster membership, as calculated in Activity Miner™
- New ‘Send to Flare’ functionality
- Improved grid view function
- Improved display of protein ribbons, offering a choice of different ribbon styles and the capability to show ribbons for the active site only
- Improved look and feel of the GUI with re-designed toolbars and updated and clearer icons for a more modern and sleek interface.
Upgrade to Forge V10.5
Upgrade at your earliest convenience to try the new Conformation Explorer and pharmacophore constraints in Forge, together with the many new and improved features in this release.
If you are not currently a Forge customer, download a free evaluation.