Properties polar surface area

Prediction of various physicochemical properties such as solubihty, lipophhicity log P, pfQ, number of H-donor and acceptor atoms, number of rotatable bonds, polar surface area), drug-likeness, lead-likeness, and pharmacokinetic properties (ADMET profile). These properties can be applied as a filter in the prescreening step in virtual screening. 

Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. I Med Chem 2000 43 3714-7. 

Polar surface area (PSA) - defined simply as the part of a molecular surface that is polar - is probably, together with the octanol-water partition coefficient, one of the most important parameters used to characterize the transport properties of drugs. PSA has been shown to provide very good correlations with intestinal... 

Absorption, in general, is treated as a physicochemical transport process based on computations of logP (the octanol/water partition coefficient) and solubility governed by factors such as polar surface area on the molecule. It is conceivable that SNPs in drug transporter genes will affect the pharmacokinetic properties of compounds and, therefore, these may have to be taken into consideration in the design process. 

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. 

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]. 

A polar surface area approximation can be calculated by summing the V, contribution of each polar atom in a molecule. A hydrophobic surface area approximation can be calculated by V) contribution of each hydrophobic atom in a molecule. More generally, for a given binary property Bt (such as is polar or is aromatic or is acceptor ) for each atom i in a molecule, an approximate surface-area based descriptor can be calculated with... 

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