Polar surface area

Caco-2 adenocarcinoma cell line derived from human colon 

Clog P calculated octanol-water partition coefficient 

HCPSA high-charged polar surface area 

QSAR quantitative structure-activity relationship SAP sum of atom polarities 

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 

Hits that are appealing to chemists as candidates for further optimization are often simple structures without excessive functionalizations this is due to the likelihood that complexity will increase during lead optimization [154]. A convenient way to gauge the potential attractiveness of a virtual library design is to compare molecular complexity scores of the virtual compounds to those calculated for hits that have been rated for their potential lead attractiveness by medicinal chemists. 

Good library designs include considerations for creating molecules that are likely to have good passive cellular permeability and intestinal absorption [157]. Polar surface 

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The MEP at the molecular surface has been used for many QSAR and QSPR applications. Quantum mechanically calculated MEPs are more detailed and accurate at the important areas of the surface than those derived from net atomic charges and are therefore usually preferable [Ij. However, any of the techniques based on MEPs calculated from net atomic charges can be used for full quantum mechanical calculations, and vice versa. The best-known descriptors based on the statistics of the MEP at the molecular surface are those introduced by Murray and Politzer [44]. These were originally formulated for DFT calculations using an isodensity surface. They have also been used very extensively with semi-empirical MO techniques and solvent-accessible surfaces [1, 2]. The charged polar surface area (CPSA) descriptors proposed by Stanton and Jurs [45] are also based on charges derived from semi-empirical MO calculations. 

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. 

Molecular volume, surface area, polar surface 3D structure Polar surface area is the... 

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. 

A similar argument can be made for electronic features such as electron density, polarization and polarizability. These are critically dependent on the ionization state of the molecule, but the conformahonal state is also highly influential. One highly approximate yet useful reflection of electron density is afforded by the polar surface area (PSA), a measure of the extent of polar (hydrophilic) regions on a molecular surface (see Chapter 5). 

Osterberg, Th., Norinder, U. Prediction of polar surface area and drug transport processes using simple parameters and PLS statistics. J. Chem. Inf. Comput. Set. 2000, 40, 1408-1411. 

HCPSA high-charged polar surface area... 

Artursson, P., Bergstrom, A. S. Intestinal absorption the role of polar surface area. 

Saunders, R. A., Platts, J. A. Correlation and prediction of critical micelle concentration using polar surface area and LFER methods. /. Phys. Org. Chem. 2004, 17,431 38. 

Investigation of the differences in crystal packing between (431) and (426) from comparison of their respective X-ray structures, revealed that (431) was more tightly packed than (442), reflected in their respective melting points of 235 and 170 °C. It was postulated that the absence of in vivo activity for (431) may be explained by the resultant reduction in water solubility and dissolution rate compared with (426). The comparatively high calculated polar surface area of (431) (122.5A ) compared with (426) (89.3 A ) was also proposed as a factor influencing the marked difference in bioavailability between the two related compounds. Compound (426) (SLV-319) is currently being developed with Bristol-Myers Squibb for the potential treatment of obesity and other metabolic disorders. Phase I trials for obesity were started in April 2004. Earlier Phase I clinical trials for the treatment of schizophrenia and psychosis, which commenced in April 2002, appear to have been abandoned. 

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