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August 01, 2011 (Vol. 31, No. 14)

Moving from Novel Target to Novel Chemistry

SAR Tools Enable Biologists to Identify Innovative Chemical Leads

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    Figure 3. Most active compounds showing conserved electron density in the terminal and central 6,5 aromatic ring systems

    Higher activity can be seen to be associated with negative (blue) Field patterns in the lower left of the presented molecule views, and was probably due to specific hydrogen bonding interactions. However, the most active compounds also presented high electron density in both the terminal and central 6,5 aromatic ring systems, as evidenced by larger negative molecular surfaces shown in Figure 3.

    The findings from this type of analysis have many uses. They can be used directly in FieldView to evaluate the likely relative activity of newly designed or competitor compounds. The structures can be drawn in FieldView rather like chemists currently doodle structures on napkins, and their activity and properties immediately evaluated. They can also be used to direct chemical synthesis into areas of the molecules most likely to deliver the desired changes in activity.

    In addition, the results can be used with virtual screening tools to identify potential bioisosteres (structurally diverse compounds with the same activity) from large compound collections.

    In the H3 example given, a field pattern selected from the most active structures was used to counterscreen an existing compound collection to identify potential H3 antagonist structures. A large number of matches were identified, with 68 distinct chemical scaffolds.

    Evaluating the level of innovation embodied in these results, the 2-D similarity score of the most interesting new molecules (measured against the most active), was found to be less than 0.7, which is the de facto cut-off for 2-D-based scoring methods. This means that most of these structures would be very unlikely to appear in a traditional library screening process as there would be no reliable way to predict their activity at that target.

    Using fields and FieldView to drive SAR analysis then, we can simultaneously be more inclusive of structural diversity and more specific about identifying the features that determine the desired activity. This can help to generate a wide set of novel chemical starting points that are generally more patentable and diverse than traditional initial screening hits.

    Biotech-based discovery teams can use FieldView to generate ideas and chemical starting points for their projects based on a solid knowledge of the biology of the novel target (whether or not its structure is available). This may help them to add more innovation and value to their chemistry assets and reduce their dependence on outsourced medicinal chemistry teams.

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