Pharmacokinetic VolSurf

Cruciani G, Pastor M and Guba W. VolSurf a new tool for the pharmacokinetic optimization of lead compounds. Eur J Pharm Sci 2000 11 Suppl 2 S29-39. 

The molecular descriptors refer to the molecular size and shape, to the size and shape of hydrophilic and hydrophobic regions, and to the balance between them. Hydrogen bonding, amphiphilic moments, critical packing parameters are other useful descriptors. The VolSurf descriptors have been presented and explained in detail elsewhere [8]. The VolSurf descriptors encode physico-chemical properties and, therefore, allow both for a design in the physico-chemical property space in order to rationally modulate pharmacokinetic properties, and for establishing quantitative structure-property relationships (QSPR). 

Calculated molecular properties from 3D molecular fields of interaction energies are a novel approach to correlate 3D molecular structures with pharmacodynamic, pharmacokinetic and physico-chemical properties. The novel VolSurf descriptors quantitatively characterize size, shape, polarity, hydrophobicity and the balance between them. 

On the basis of their evaluation and our internal predictive VolSurf model [160] for this series (r 0.81, q 0.60, 4 PLS components), it can be concluded that factors like size and shape, which had previously been reported to affect paracellular permeability, are indeed important in the VolSurf PLS model to explain the local structure-permeability relationship of one particular scaffold. Hence, local statistical models provide a qualitative ranking of candidates, and thus are valuable for optimization of pharmaceutically relevant compounds, especially if combined with additional models to understand affinity, selectivity or any particular pharmacokinetic behavior. 

The approach discussed to use VolSurf derived in silica models to understand structure-PK relationships for pharmacokinetic properties was also applied to one series of selective cardiac KATP channel blockers [160]. It was found that compounds fulfilling the predefined selectivity profile exhibit only less-optimal pharmacokinetic properties because of a short plasma mean residential time (MRT). Consequently, the MRT for 28 compounds from rabbit iv studies for one series was used as dependent variable to derive a VolSurf PLS model in addition to ligand affinity SAR data. The chemical... 

Fig. 14.12 VolSurf model to correlate 49 matrix metalloproteinase inhibitors with different zinc-binding functionalities to rabbit oral bioavailability for metabolically stable compounds. (A) Semiquantitative PLS model 0.424, r 0.646, 4 PLS components) to rank novel synthesis candidates. Main factors influencing absorption, that is, lower polarity, capacity factors and increased hydrophobicity, are in agreement with global models for human intestinal absorption. (B) Distribution of polar and hydrophobic surfaces for two molecules with low (0981) and higher (2290) rabbit AUC from oral pharmacokinetic studies.

Crudani, G., Clementi, S., Crivori, P., Carrupt, P.A. and Testa, B. (2001) VolSurf and its interest in structure-disposition relations, in Pharmacokinetic Optimization in Drug Research Biological, Physicochemical and Computational Strategies (eds B. Testa, H. van de Waterbeemd, G. Folkers and R.H. Guy), Wiley-VCH, Weinheim, pp. 539-550. 

Mannhold, R., Berellini, G., Carosati, E. and Benedetti, P. (2006) Use ofMlF-based VolSurf descriptors in physicochemical and pharmacokinetic studies, in Molecular Interaction Fields (ed. G. Crudani), Wiley-VCH, Weinheim,... 

Several papers have also been published in which a correlation has been sought between permeation across Caco-2 cells and physicochemical properties of the compounds. The review article by Ekins et al. (2000) discusses several studies to predict Caco-2 cell permeation. Correlations have been found with polar surface area, hydrogen bond descriptors, VolSurf, and other parameters. Van de Waterbeemd et al. (2001a) also discuss models for predicting oral absorption of compounds, including the use of Caco-2 cell lines. This paper also provides much useful information on the optimization of pharmacokinetic parameters in drug development. 

Cruciani G, Crivori P, Carrupt PA, Testa B (2000) Molecular fields in quantitative structure-permeation relationships The VolSurf approach. Theochem 503 17-30 Cruciani G, Pastor M, Clementi S (2000) Handling information from 3D GRID maps for QSAR studies. In Gun-dertofte K, Jorgensen FS (eds) Molecular modelling and prediction of bioactivity, proceedings of the 12th European symposium on quantitative structure-activity relationships (QSAR 98). Plenum Press, New York, pp 73-81 Cruciani G, Pastor M, Guba W (2000) VolSurf A new tool for the pharmacokinetic optimization of lead compounds. Eur J Pharm Sd 11 S29-S39... 

Use of MIF-based VolSurf Descriptors in Physicochemical and Pharmacokinetic Studies... 

Alternatively, calculated molecular properties from 3D molecular fields of interaction energies represent a valuable approach to correlate 3 D molecular structures with physicochemical and pharmacodynamic properties. In contrast, their use in correlations with pharmacokinetic properties is still poorly explored and exploited. The rather new VolSurf approach [5-7] is able to compress the relevant information present in 3D maps into a few descriptors characterized by the simplicity of... 

In the following we describe successful applications of the updated VolSurf software in modeling physicochemical and pharmacokinetic drug properties, comprising aqueous solubility, octanol/water partition coefficients, volume of distribution, and metabolic stability. 

In the present chapter, we have used an updated version of the VolSurf procedure to exemplify its validity for predicting physicochemical (solubility and log P) and pharmacokinetic properties (volume of distribution and metabolic stability) of drug molecules. 

---