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We can apply the same principles to screening for lead candidates, regardless of whether it is virtual screening or high-throughput screening. While both are reasonable screens, each can be plagued by very low positive-predictive values (despite low false-positive rates), particularly when applied to all available compounds, or large virtual libraries. We want to use simple filtering techniques to focus the set of compounds passed on to more computationally intensive screening methods. First, we can consider filtering based on functional groups. Generally speaking, there are toxic and reactive functional groups that we simply don't want to consider (alkyl-bromides, metals etc). Next, there are functional groups that aren't strictly forbidden, but are not desired in large quantities. For instance, parafluoro-benzene, or trifluoromethyl have specific purposes, but heavily fluorinated molecules can be eliminated.
Beyond simple functional group filtering, one can consider both simple and complex physical properties which can be used to characterize the kinds of compounds one would like to keep and those one would like to eliminate. These properties attempt to consider "drug-likeness", such as bio-availability, solubility, toxicity, and synthesizability even before the primary high-throughput or virtual screening, which primarily are geared toward detecting potency alone. The best known of the physical property filters is Lipinski's "rule-of-five", which focuses on bioavailability [1]. However, many other physical properties, such as solubility, atomic content, ring structures, and surface area ratios can also be considered. We provide algorithms for calculating many of these properties, and apply them with filters based on literature studies.
Finally, one should eliminate the types of compounds that can be troublesome at later stages. For instance, Shoichet's aggregating compounds often produce false positives that can waste enormous resources if they were identified by virtual or high-throughput screening [2,3]. Similarly (and sometimes concomitantly) dyes can appear to be inhibitors by interfering with colorimetric or fluorometric assays or binding non-specifically to the target protein.
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