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.
The primary utility of a hybrid program is
in denovo ligand generation. Figure 11 depicts how these programs
work. In the upper left hand corner of this figure, we see an active site
with three distinct regions colored in blue, green, and red. The goal of a hybrid program is to generate a
complete ligand that complements the active site region. To do so, these
programs employ a combination of scanner and builder algorithms in divide and
conquer approach. These programs first utilize scanner technology to find
components that will complement individual subsites within the active site
volume. This is depicted by the components in the blue, green, and red boxes. These individual components are then
docked into their respective regions within the active site as shown in the
upper right. Splicing fragments, shown in purple, are then used to join these components into a
single complete ligand. It is important to note that numerous possible
fragments may exist that complement the various active site regions. Thus,
a potentially large number of ligands may be generated by combinatorially
linking the various components.
Figure 11. Overview of hybrid-type programs.
As stated above, hybrid-type programs are mainly used for denovo generation of lead compounds. The strength of these programs is in their ability to generate a large number of diverse potential hits. However, they suffer the same shortcomings as all denovo design packages described above. The difficulties in accurately calculating ligand receptor binding affinity are significant. In addition, the combinatorial nature of the algorithm often leads to the generation of chemical structures that are undesirable, unstable, or synthetically difficult. Finally, the developer of the software may bias the generation of compounds. For example, many of these programs place components within the active site using a pre-determined binding algorithm based upon the functional groups that are presented by the receptor. Additionally, the algorithms used to splice the components together greatly affect the generated ligands.
Prev - Conformational Searching
Next - Component Extraction
Return to RACHEL Technology - Main
(c) 2002 Drug Design Methodologies, LLC. All Rights Reserved