Lead Optimization Overview Tutorial

The Lead Optimization Module involves everything from library enumeration to affinity prediction. Lead optimization occurs throughout the design-make-test-analyze (DMTA) cycle.

A general progression of investigation in this module is as follows.

1. Run a Focused Library enumeration floe. The Focused Library – Molecule Input floe is recommended. It applies reactions to the input lead molecule, generating an output dataset of products.

2. Run a docking floe such as Gigadock Warp Floe.

3. Filter hits with the Filter Docking Hits by Interactions Floe. This floe annotates docking results with interactions to enable filtering by interactions using the dataset filters in Orion and calculates an interaction fingerprint with respect to the cognate ligand in the receptor. This can help more easily identify dissimilar ligands with similar binding modes.

4. Run the Short Trajectory MD with Analysis (STMD) and Nonequilibrium Switching (NES) Floes. STMD is used primarily for pose validation. This floe performs MD simulations given a prepared protein and a set of posed and prepared ligands, running both bound and unbound simulations of each ligand, then analyzes the bound trajectory for pose stability. The output datasets can be used as input for NES floes. NES calculates the relative binding affinities (RBFE) of a given target and its ligands.

Note

More detailed module-level tutorials will be provided in a later release.