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ProteinSpectrumScreen

Detects potential moderate-to-serious adverse activity, additional unexpected activity and broad relative selectivity for a library of compounds by screening them against several hundred of the ADME/Tox-Asssociated human proteins. This procedure helps prioritize the development of drug candidates.

BACKGROUND: ProteinSpectrumScreen includes the following packages:

· Human Toxicology and Drug Resistance - 217 proteins

· Human Drug Metabolism - 63 proteins

· Human Angiogenesis - 60 proteins

· Human Stress, Toxicity and Response to Cellular Damage - 78 proteins

· Human Extracellular Matrix and Adhesion Molecules - 69 proteins

· Human Drug Targets for Inflammation and Immunomodulation - 72 proteins

· Adverse and additional effects - 123 proteins

You can see a fragment of one of the packages on this figure (See Fragment of ProteinSpectrumScreen):

Fragment of ProteinSpectrumScree

Opening a Library

Open a library of compounds that need to be screened against proteins: File->Open Library... (for more details regarding working with library, see the Library Screening module of this User Manual).

Selecting Proteins

Select Tools->ProteinSpectrumScreen. The following window will appear (Figure 45):

Figure 45 - Protein Database

Click on the checkboxes to select proteins for screening. The number of selected proteins can be seen in the bottom of the window.

The same window also allows the following options:

· add a new protein structure to the database - use the Add New Proteins... button;

· visualize the 3D structure of a protein (in our case CYP450, 3A4) - use the View button; and

· choose all proteins for screening - use the the Select All button.

Screening Results

As soon as all the selected choices are complete, each compound from the library automatically docks to each of the selected proteins. The results of the calculations are shown in the following form (Figure 46):

Figure 46 - Results

For each compound, we have the number of weak, moderate and strong binding affinity reactions with the list of proteins

Use the sort option (Figure 47) to compare compounds regarding their relative selectivity, strong activity etc.

Figure 47 - Sort

If you click on a compound, the following window appears (Figure 48):

Figure 48 - Results per Compound

This information allows you to get the IC50s of each protein from the list.

This window also gives the following options:

· visualize the 3D structure of a protein with the ligand - use the View button;

· sort by column - use the Sort button; and

· save a report in HTML format - use the Save Report...button.

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