An atomic surface site interaction point description of non-covalent interactions.

Molecular electrostatic potential surfaces (MEPS) calculated using density functional theory have been used to develop a simplified description of the non-covalent interaction properties of organic molecules. The Atomic Interaction Point (AIP) model introduced here represents an evolution of the Surface Site Interaction Point (SSIP) model described previously, in which a molecule is represented by a discrete set of interaction points that define sites of interaction with other molecules. The interaction sites are described by interaction parameters that are equivalent to the experimentally determined H-bond donor and acceptor parameters and .

An empirical model for solvation based on surface site interaction points.

Surface site interaction points (SSIP) provide a quantitative description of the non-covalent interactions a molecule makes with the environment based on specific intermolecular contacts, such as H-bonds. Summation of the free energy of interaction of each SSIP across the surface of a molecule allows calculation of solvation energies and partition coefficients. A rule-based approach to the assignment of SSIPs based on chemical structure has been developed, and a combination of experimental data on the formation of 1 : 1 H-bonded complexes in non-polar solvents and partition of solutes between different solvents was used to parameterise the method.

Ionization-specific analysis of human intestinal absorption.

This study presents a mechanistic QSAR analysis of human intestinal absorption of drugs and drug-like compounds using a data set of 567 %HIA values. Experimental data represent passive diffusion across intestinal membranes, and are considered to be reasonably free of carrier-mediated transport or other unwanted effects. A nonlinear model was developed relating %HIA to physicochemical properties of drugs (lipophilicity, ionization, hydrogen bonding, and molecular size).

Predicting penetration across the blood-brain barrier from simple descriptors and fragmentation schemes.

The ability to cross the blood brain barrier (BBB), sometimes expressed as BBB+ and BBB-, is a very important property in drug design. Several computational methods have been employed for the prediction of BBB-penetrating (BBB+) and nonpenetrating (BBB-) compounds with overall accuracies from 75 to 97%. However, most of these models use a large number of descriptors (67-199), and it is not easy to implement the models in order to predict values of BBB+/-.

Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol/water and immobilized artificial membrane lipophilicity.

A fast gradient HPLC method (cycle time 15 min) has been developed to determine Human Serum Albumin (HSA) binding of discovery compounds using chemically bonded protein stationary phases. The HSA binding values were derived from the gradient retention times that were converted to the logarithm of the equilibrium constants (logK HSA) using data from a calibration set of molecules. The method has been validated using literature plasma protein binding data of 68 known drug molecules.

Application of hydrogen bonding calculations in property based drug design.

A drug can be characterized by "descriptors" that include size (volume) and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g.

On the mechanism of human intestinal absorption.

In order to investigate whether the main step in intestinal absorption in humans is dominated by partition or by diffusion, we have transformed % human intestinal absorption into a first-order rate constant, and have regressed the latter, as logk, against our solvation parameters. The obtained regression coefficients are compared with those for diffusion and partition processes. The coefficients in the logk equation are completely different to those for water/solvent partitions, but are very similar to those for processes (not involving transport through membranes) in which diffusion is the major step.