Hydrogen polar surface area

One of the simplest and most common ways to evaluate a molecule for ADME properties is a qualitative examination of its basic descriptor values such as molecular weight (MW), ClogP for lipophilicity, polar surface area (PSA), counts of hydrogen bond donors and acceptors (HBD, HBA), and count of rotatable bonds (RB). This type of approach popularized by Lipinski s famous Rule of 5 was published a decade ago [6]. Lipinski et al. established cutoffs for MW (500), ClogP (5), HBA (10), and HBD (5). These cutoffs were based on the 90th percentile of distributions of molecules in the World Drug Index having USAN or INN names. The Rule of 5 considers a violation of any two of these cutoffs to be an alert for poor absorption or permeability. 

Hydrogen bonding descriptors the counts of hydrogen bond acceptors (HAG) or donors (HDO) the number of polar atoms, Pjt [34] the polar surface area in (PSA) and normalized to the total surface area (%PSA) ... 

As mentioned above, hydrogen bonding and molecular size, in combination with lipophilicity have an important influence on oral absorption. A number of methods are available to compute these properties. A further example of the correlation between H-bonding, expressed as polar surface area, is found in Figure 3.12 [24,25]. Such a sigmoidal relationship is found for compounds which are absorbed by passive diffusion only and not hindered by efflux or metabolism, and which are not involved in active uptake. Otherwise deviations will be foimd [25]. 

Click on the Compute button to calculate physiochemical properties including the number of hydrogen bond acceptors and donors, XlogP (partition coefficient) values, molecular weights, number of rotatable bond, and the Topological Polar Surface Area (TPSA) of compounds. 

Calculated properties were restricted to ClogP <3, the number of rotatable bonds <5, the number of hydrogen bond acceptors (HBA) <4 and the number of hydrogen bond donors (HBD) between 1 and 3. The topological polar surface area (TPSA) was set to <70 A2. In addition, a special feature count excludes structures that are too functionalised (feature rich) or dull (absence of pharmacophoric interaction points). This feature count is the sum of HBA, HBD and the number of five-and six-membered aromatic rings and selection was restricted to fragments with a feature count in the range 4-7. 

Other attempts to refine or improve Lipinski s rule set have appeared in the literature. One notable factor for consideration is the number of rotatable bonds in a hit. Increased molecular flexibility can reduce the ability of a molecule to cross a membrane. The maximum number of rotatable bonds has been suggested as 10. The polar surface area, often abbreviated as PSA, of a molecule is another important factor. Polar surface area is tightly correlated to the number of hydrogen-bond donors and acceptors contained in a molecule. A maximum polar surface area of 140 A2 or the equivalent of 12 hydrogen-bond donors/ acceptors has been suggested. This is in line with Lipinski s rules.22... 

These model compound studies provide us with estimates of the first two fundamental parameters of ACp ap = 0.45 cal K-1 (mol A2)-1 of buried apolar surface area and ACPjpoi = — 14.3 cal K-1 moT1 of hydrogen bonds. The average polar surface area buried per hydrogen bond in globular proteins is 54 7 A2 (see below) so that ACp>poj = - 0.26 cal K-1 (mol A2)-1 of buried polar surface. 

Based on the range of enthalpy values for hydrogen bonding, the polar contribution to AH° of denaturation should be between 1.5 and 3.3 kcal mol-1 of hydrogen bonds at 25°C. This corresponds to values ranging between 27.5 and 60.4 cal (mol A2)-1 of buried polar surface area. Estimation of the fundamental parameter A//+ requires the additional specification of TA because ACp>poi is not zero, as discussed above. 

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