Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

Delivery of therapeutic proteins into tissues and across the blood-brain barrier is severely limited by the size and biochemical properties of the proteins. Here it is shown that intraperitoneal injection of the 120-kilodalton β-galactosidase protein, fused to the protein transduction domain from the human immunodeficiency virus TAT protein, results in delivery of the biologically active fusion protein to all tissues in mice, including the brain. These results open new possibilities for direct delivery of proteins into patients in the context of protein therapy, as well as for epigenetic experimentation with model organisms.

https://science.sciencemag.org/content/sci/285/5433/1569.full.pdf

In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse

Molecular polar surface area (PSA), i.e., surface belonging to polar atoms, is a descriptor that was shown to correlate well with passive molecular transport through membranes and, therefore, allows prediction of transport properties of drugs. The calculation of PSA, however, is rather time-consuming because of the necessity to generate a reasonable 3D molecular geometry and the calculation of the surface itself. A new approach for the calculation of the PSA is presented here, based on the summation of tabulated surface contributions of polar fragments. The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA (the correlation coefficient between 3D PSA and fragment-based TPSA for 34 810 molecules from the World Drug Index is 0.99), while the computation speed is 2-3 orders of magnitude faster. The new methodology may, therefore, be used for fast bioavailability screening of virtual libraries having millions of molecules. This article describes the new methodology and shows the results of validation studies based on sets of published absorption data, including intestinal absorption, Caco-2 monolayer penetration, and blood-brain barrier penetration.

https://peter-ertl.com/reprints/Ertl-JMC-43-3714-2000.pdf

Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of Drug transport properties

http://academic.oup.com/milmed/article-pdf/146/7/506/24126715/milmed-146-7-506.pdf

Goodman and Gilman's The Pharmacological Basis of Therapeutics

Caco-2 monolayers in experimental and theoretical predictions of drug transport

The influence of physicochemical properties, including lipophilicity, H-bonding capacity and molecular size and shape descriptors on brain uptake has been investigated using a selection of marketed CNS and CNS-inactive drugs. It is demonstrated that the polar surface area of a drug can be used as a suitable descriptor for the drugs' H-bonding potential. A combination of a H-bonding and a molecular size descriptor, i.e., the major components of lipophilicity and permeability, avoiding knowledge of distribution coefficients, is proposed to estimate brain penetration potential of new drug candidates. Previously reported experimental surface activity data appear to be strongly correlated to molecular size of the drug compounds. Present analysis offers a modern basis for property-based design and targeting of CNS drugs.

Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors.

Permeability of a compound by passive diffusion through a biological membrane such as Caco-2 cell monolayers depends mainly on lipophilicity, molecular size and hydrogen bonding capacity of the solute. Since these properties are often used in structure-permeability correlations, we have evaluated different calculated descriptors for size and hydrogen bonding, as well as their intercorrelations. A new descriptor for hydrogen bonding potential is introduced. It is demonstrated that a combination of appropriate size and H-bonding descriptors using graphical or Eq.-based approaches may be of potential use for membrane permeation estimation.

Estimation of Caco‐2 Cell Permeability using Calculated Molecular Descriptors

Partial atomic charges are significant descriptors in predicting the water solubilities of crystalline organic compounds from their chemical structures. Lipophilicity remains the predominant factor. It was also found that quantitative estimates of hydrogen bond strengths (hydrogen bond factors) play important roles. These descriptors can be easily interpreted to guide chemists to the synthesis of compounds with increased or decreased water solubility. This work is based on a set of 22 compounds the aqueous solubilities of which were determined by a new potentiometric method, pSOL, and were confirmed, in part, by the traditional shake-flask method. A new software package, HYBOTPLUS, furnished the partial atomic charges and hydrogen bond factors.

Oleg A. Raevsky

Papers

Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors.

Estimation of Caco‐2 Cell Permeability using Calculated Molecular Descriptors

Estimating the water solubilities of crystalline compounds from their chemical structures alone.

Quantitative Estimation of Drug Absorption in Humans for Passively Transported Compounds on the Basis of Their Physico‐chemical Parameters

Quantitative estimation of hydrogen bond contribution to permeability and absorption processes of some chemicals and drugs