Since the 1990s, dozens of rational drug design packages have been published. These programs fall in one of three main genres: 1. Scanners, 2. Builders, or 3. Hybrids.
Figure 8A. Overview of database search programs.
All database search programs fall into this category. Scanner type programs are more or less used for lead compound screening. Figure 8A shows how these programs are utilized. In the upper left corner, we see an active site with a lead compound whose binding structure has been determined. From biochemical analysis of the ligand-receptor interaction, we determine that three ligand groups make up the pharmacophore: a phenyl ring (green), an amide hydrogen (blue), and a hydroxyl group (red). The pharmacophore is transformed into a query that specifies the three-dimensional relationship between the various functional groups desired. A database of compounds is then utilized whose three-dimensional structures are known. The query is then used to search the database for compounds that mimic the pharmacophore and can potentially bind to the receptor target. Example results are shown in Figure 8B below.
Figure 8B. Database search results.
Database search programs have inherent strengths. To begin, the user has complete control over the query specifications. This allows for the retrieval of structures that meet the requirements of the pharmacophore and have a better opportunity to complement the receptor. Secondly, because these programs utilize a database of known compounds, synthetic feasibility is not an issue. In addition, these programs are usually highly optimized for speed, which allows for the rapid determination of potential binding ligands. Finally, since compounds are retrieved that mirror the query, no scoring functions are required. The assumption is that the three-dimensional structure stored in the database is representative of biological reality. Although this can be true of small molecules, larger structures are often too flexible for the assumption to hold true.
Database search programs also have inherent weaknesses that limit their application. First and foremost, a database of structures is required. Although pharmaceutical companies are likely to maintain corporate databases, many academic institutions lack the manpower and funding to generate this wealth of data. Secondly, the database has a finite number of structures, which limits and biases potential solutions. Finally, there is no recombination or derivatization of retrieved structures, which builder-type programs exhibit. Thus, the diversity of potential hits is limited as well.
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