Run virtual screens

Ligand-based virtual screening

Virtual screening remains one of our most consistently requested projects. By using Blaze™ your project will benefit from excellent enrichments, and the chemotype diversity output is second to none. Blaze relies on two very simple premises:

1. A bioactive conformation encodes, in its shape and electrostatic field, both the properties, recognition features and solvation pattern optimized for interaction with its protein target site.
2. A molecule conformation with increasing ‘shape and field’ similarity to that bioactive conformation has an increasing probability of also being active.

The key determinants of real activity obtained from hit lists (other than was this truly the ‘bioactive conformation’?) is often just how relevant and what distribution that hit conformation has in the population. This is fundamentally why our ligand-centric screening invariably works extremely well. Given that a molecule can adopt a similar shape, and project the same electrostatic patterns, from a completely different chemical architecture, leads to a very diverse output.

Structure-based virtual screening

When preparing ligands for virtual screening in Blaze, we use modeling to help define the best ‘hand-crafted’ estimate of a bioactive conformation, based on the widest data for any given system. The same care to exploring and preparing protein targets prior to structure-based virtual screens is applied. We take advantage of three main approaches to advance your project:

1. Lead Finder™ includes the excellent Build Model protein preparation tool.
2. Proteins and ligands are modeled using the same proprietary XED force field used to give the accurate electrostatics that all Cresset software is based on.
3. Access to the very latest Cresset software gives us the ability to provide protein electrostatic field maps and water analysis, providing a very reliable starting position for structure-based virtual screening.

What are the advantages of structure-based and ligand-based virtual screening, and how do we choose which is the best approach for your project?

Ligand-based virtual screening is less computationally intensive, making it a preferred option when there is a known ligand available. An average protein of 400 amino acids has over 20,000 heavy atoms and 9,600 bonds and in excess of 50 charges, making it a more challenging system to model.

However, even when there is a known ligand there are some situations when a ligand-based virtual screening is not viable, such as when the known ligand does not exploit all the interactions available in an active site or when a protein has an unattractive orthosteric site and attractive allosteric sites with no known ligands. In these cases, we prefer to use a structure-based method.

In the case of protein-protein interaction sites and protein-DNA/RNA sites, Blaze can take DNA and protein fragments as a template in place of a ligand. However, it is useful to have a structure-based approach available for comparison.

In fact, we often find it useful to combine different virtual screening techniques. In lead discovery, one of the key requirements for virtual screening is to maximize the diversity of hits returned.  All virtual screening techniques, be they ligand-based or structure-based, are probabilistic techniques in that they may be used to increase the likelihood of getting hits from a wet screen. No technique guarantees to give absolute binding energies (at least not in the context of virtual screening on any realistic size of screening library), but they do give good rank ordering of compounds and can, therefore, be used as a means of selection and prioritization.

Ligand-based techniques, whether 2D or 3D, are algorithmically distinct from structure-based techniques such as docking and, therefore, give different rankings to compounds. Different approaches return different hits and the results can be combined into an enriched final list.

Combining the results of structure-based and ligand-based techniques provides further diversity, leading to better hit rates and more interesting hits.

Your one-stop shop for virtual screening

Cresset Discovery has the most comprehensive virtual screening capabilities available in the computational chemistry outsourcing industry.

Contact us for a free confidential discussion.