Non-polar surface area

B, C, and D are constants, the electrostatic term is expressed by A = Dfi/RT in which fl is the dipole moment of the protein, and the hydrophobic term is expressed by Q, = [N + 4.8N1 3V2/3(Ke -1)]/RT, where N is Avogadro s number, is the non-polar surface area of the protein, V the molar volume of the solvent, and <7 is the surface tension increment, i.e., the difference between the surface tensions with and without salt x6 is a correction factor for the surface tension to take account of the curvature of the protein surface at molecular dimensions. 

Figure 8.1 shows that the properties that Abbot scientists predicted most frequently for their compounds, using their WWW portal, are structural alerts for toxicity and mutagenicity. " The second largest number of predictions is for log P followed by bioavailability scores (rule of five and internal Abbot score ), p.Ka, and solubility prediction as well as prediction of some other more complex properties, such as Blood Brain Barrier (BBB) permeability, binding energy, polar/non-polar surface area, and log D. 

Andrews Binding Energy Polar/Non-Polar Surface Area 3D Clark log(brain/blood)... 

Although the Dj and MAP equations have different forms, the dominant terms are exceptionally consistent. In the MAP model non-polar surface area and curvature are the properties used, while in the Dj model the highest-weighted descriptors are surface area and pocket compactness (which correlates with curvature). 

Fig. 1. Sigmoidal correlation between human fractional dose absorption and PS Ad for 20 drugs (data from Palm et al. 1997). The influence of the polar surface area on fractional absorption is illustrated by comparing PSA regions for the orally available nordiazepam (left) to the non-available lactulose (right).

Figure 6.1. Distribution of polar surface area for 776 orally administered CNS drugs (black bars) and for 1590 orally administered non-CNS drugs (white bars) that have reached clinical phase II efficacy studies (35).

FIGURE 12.1 Distribution of the polar surface area (A) for drugs that have reached at least Phase 11 efficacy studies. Panel A 776 orally administered CNS drugs. Panel B 1,590 orally administered non-CNS drugs. ... 

Amide or urea formation is frequently used as a key reaction in the synthesis of prospective chemistry arrays due to the simplicity of the chemistry and the availability of building blocks. However, the polar surface area (PSA) of amides 1 and 2 and ureas 3 and 4 was calculated to be in the range 80-95, which is generally considered to be too high for good CNS penetration [14]. Non-amide analogues with a lower polar surface area such as the benzimidazole S (tPSA (Ertl) = 58) have also been reported [15],... 

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