This spectrum of tools allows one to pare down the number of virtual compounds using a combination of synthetic complexity and interaction scores to hundreds and thousands of virtual ligands employing SPROUT (and or TOPOMAX) with confidence that the complexity triage is indeed linked to the `ease of synthesis’. Virtual high throughput screening requires the use of approximate approaches to distinguish the complimentarity of ligands to target. I am a guy that early on naively believed that docking solutions relying on physics based approaches, for example carefully developed charge sets (1-6-12 potentials) could get me there. After all, I have done numerous MD simulations and employed MMPBSA approaches to estimate binding free energies to good effect(Proteins 55:895-914). High throughput docking, employing the 3D structures of ligand and targets, however, provides a facile first approach to glean principles for ligand recognition of targets.

The matrix below shows an example of such a hypothetical screen to examine how each of the native ligands of 13 targets score against targets in the same or distinct pharmacological families.
These chemical features in the binding site landscape constitute features that may be exploited in the molecular design process to optimize the affinity of a virtual ligand to a target. With addition of more fragments to the initially designed de novo leads, the affinity may improve substantially.
There are cases, however, in which assumptions about the possible locations of binding hot spots are difficult or should be avoided altogether. Then, the box is “flooded” with a virtual fluid to detect all the cavities which will define the binding surface.

Often, however, one wants to survey the synthetic accessibility of a large database of `virtual compounds’ ranging from with hundreds to hundreds of thousands of compounds.
Considerable experimental and computational evidence suggests that the pi-cation interactions are a substantial contribution to the binding free energy of these ligands to AChBP.

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