Identify new chemical series

There are different tools and tricks to finding a new chemical series, but they all involve setting up a screen. The differences lie in the input data available for setting up the screen, and the type of screen you choose – virtual, biochemical or biophysical. Cresset Discovery specializes in virtual screening, whether the starting point is ligand or protein data.

When the protein and the ligand are both known

The ideal scenario is when the protein and the ligand are both known. A recent Cresset Discovery project had just this scenario – we had both sides of the equation. We brought the two sets of information together and used them as a virtual screening seed to find new chemistry. We were able to carry out a virtual screen that identified a compound with the same electrostatics and shape as the first series, but which was a new chemical entity. This provided an ideal back-up series for the customer.

Without doubt, if you know the protein-ligand interaction, then using it to carry out a virtual screen is absolutely the best method for finding a new chemical series, and Cresset Discovery is expert in carrying out this work. Many projects do not have such complete starting knowledge, but it is often possible to deduce a ligand protein interaction from analyzing either the ligand or the protein data.

Starting from the protein

When the protein is known, the focus is the binding pocket. The goal is to find something that will bind into the pocket that will lead to a pharmacological effect; there is no point in binding in a way that doesn’t change its function. The new entity must activate or deactivate the protein in a way to bring about the desired pharmacological effect.

Docking is the process of looking for a ligand that has complementary shape, electrostatics and H-bonding patterns to interact with the binding pocket. The overall dipole must also match.

Protein preparation is vital to success. If a ligand is available in a bound state, then it may be possible to determine whether the protein is in an ‘active’ or ‘inactive’ state. The residues must be in positions consistent with the binding mode, and any waters that are important for binding must also be considered. Cresset have conducted an extensive review of protein docking tools and have concluded that Lead Finder is a valuable tool for structure based virtual screening work.

The virtual screen is mainly based on a shape fit. Molecules are scored on how well they fit and also on whether they have good interactions or clashes in terms of the electrostatics. The result is a score that can be used to prioritize output for purchase.

The ligand-only route

In the absence of a protein structure we use a ligand-centric method to find something that forms a good match to that ligand. If ligand-only SAR is available, then all of your molecules can be aligned together in a way that makes sense of the activity data.

Cresset Discovery uses the XED force field to analyse the electrostatics, hydrophobicity and shape of the ligands to produce an alignment hypothesis that is consistent with the data and that can be used in the virtual screen.

Virtual screening focuses your biological screening

Running biochemical or biophysical screens involves the selection and purchase of a library of compounds to screen against your assays. Typical screens include a hundred thousand compounds, which is an expensive and not very thorough way of exploring chemical space. The number and diversity of purchasable chemical space is orders of magnitude in excess of this.

Cresset Discovery can screen against millions of virtual screening compounds. We regularly run experiments that use a large computational cluster to compare 10 million compounds in a few days. We can carry out a conformational sampling of all available commercial compounds. We can dock them and score them. Our goal is to cut down the field of 10 million commercially available compounds to tell you which are the best 1000 or so compounds to focus on. A wet screen would still be necessary, but only to screen those compounds that are most likely to be active.

This streamlined method is a very cost effective way of finding new chemical series. Adding in silico work enables a short cut through the process, making it far more streamlined and cost effective.