Figure 2.25 • Diagram of a hypothetical receptor site, showing distances between functional groups.
Rule of Five.41,42 A candidate molecule is more likely to have poor absorption or permeability if:
1. The molecular weight exceeds 500.
2. The calculated octanol/water partition coefficient exceeds 5.
3. There are more than 5 H-bond donors expressed as the sum of O-H and N-H groups.
4. There are more than 10 H-bond acceptors expressed as the sum of N and O atoms.
Because of misses when searching or mining databases, there have been two suggested changes. The first of these is to take into account the fact that many compounds will be significantly ionized at physiological pH and, therefore, use the distribution coefficient log D with an upper limit of 5.5 rather than a log P of 5.43 Similar results have been found when evaluating herbicides and pesticides.44 A second suggested modification of the Rule of Five gives specific ranges for log P, molar refractivity, molecular weight and number of atoms (Table 2.10).45
The rapid evaluation of large numbers of molecules is sometimes called high-throughput screening (Fig. 2.26). The screening can be in vitro, often measuring how well the tested molecules bind to cloned receptors or enzyme active sites. Robotic devices are available for this testing. Based on the results, the search for viable structures is narrowed, and new compounds are synthesized. The criteria for activity will be based on structure and physicochemical values. QSAR, including 3D-QSAR, models can be developed to aid in designing new active ligands.
Alternatively, the search may be virtual. Again starting with the same type of database and the dimensions of the active site, the ability of the compounds in the database to fit or bind is estimated. The virtual receptor will include both its
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