Profiling 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. 

Fig. 10.5. Virtual product property profiling within PGVL Hub. The upper threshold for cLogD and the lower threshold for c LogS were determined from Spotfire analysis of 2-aminoacetamide lead series. The upper threshold values for MW, number of rotatable bonds (NRB), and polar surface area (TPSA) were user-specified parameters. The rest of the thresholds (e.g., lower threshold for calculated LogDat pH 7.4 or the upper threshold for calculated Log of solubility) are either the lowest or the highest property values of the virtual products.

The legacy aqueous thermodynamic solubility model is an in-house linear regression model consisting of 11 calculated descriptors which include cLogP and polar surface area. This is the model that was used to shape the property profile of the virtual products. This model has now been superseded by a Cubist (48) thermodynamic solubility model (R2 =... 

Novartis uses the In Silico Profiling web tool. Available properties include the octanol water partition coefficient log P, molar refractivity, flexibility index, hydrogen bonding characteristics and molecular polar surface area. Various drug properties, such as intestinal absorption, BBB permeability or Plasma Protein Binding (PPB) are calculated based on in-house models. 

An excellent example of modern day multi-parametric lead optimization, in the absence of target protein structure, is described by Pinard et al., who balanced pharmacological in vitro hGlyTl uptake inhibition), physicochemical (calculated LogP (cLogP) and polar surface area (PSA)), pharmacokinetic (mouse brain versus plasma concentration) and safety (hERG) profiles in order to deliver an impressive GlyTl inhibitor clinical candidate. ... 

A whole series of orthonormal functions can be used to interpret the information. The most familiar and applicable are the Fourier functions. Before being able to compose a particle shape descriptor in the polar system by the use of Fourier functions, one must realize that all that is normally known of a particle is its silhouette or profile. Therefore, methods must be found to interpret information from cuts through the particle or scans of portions of the surface area and connect it with overall shape. It is assumed that the silhouette of any cut or sample of the surface will give all information, such as roughness and other physical parameters, needed to describe the entire particle surface. Thus, unless the silhouette of a particle misses a unique, dominant feature of the particle shape, it will be representative of the particle. By sampling... 

Figure 1. Series of CV profiles for Rh in 0.5 M aq H2SO4 solution taken at the sweep rate s = 50 mV s" the electrode real surface area equals 0.26 0.01 cm. The profiles demonstrate samples of the effect of increase of the polarization potential, Ep, from 1.10 to 1.35 V, RHE, on the oxide thickness while sustaining T constant at 298 K and the polarization time, tp, at 1000 s. The CV o dde-reduction profiles reveal only one oxide state, OCl, which shifts towards less-positive potentials.

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