Iterative Refinement of a Binding Pocket Model: Active Computational Steering of Lead Optimization

Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143-0912, United States.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 10/2012; 55(20):8926-42. DOI: 10.1021/jm301210j
Source: PubMed


Computational approaches for binding affinity prediction are most frequently demonstrated through cross-validation within a series of molecules or through performance shown on a blinded test set. Here, we show how such a system performs in an iterative, temporal lead optimization exercise. A series of gyrase inhibitors with known synthetic order formed the set of molecules that could be selected for "synthesis." Beginning with a small number of molecules, based only on structures and activities, a model was constructed. Compound selection was done computationally, each time making five selections based on confident predictions of high activity and five selections based on a quantitative measure of three-dimensional structural novelty. Compound selection was followed by model refinement using the new data. Iterative computational candidate selection produced rapid improvements in selected compound activity, and incorporation of explicitly novel compounds uncovered much more diverse active inhibitors than strategies lacking active novelty selection.

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    • "Still another area for exploration is the degree to which, given molecules with low to mid-range potency for training, that the method is able to help “climb the hill” toward more potent molecules. Given the strong dependence on molecular alignment, this may prove to be challenging, though active selection of structurally novel compounds (irrespective of their predicted potency) offers a strategy that was beneficial in the case of bacterial gyrase [17]. With large and diverse data sets that span long time periods becoming increasingly available, we believe that it will be possible to systematically investigate this question. "
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