Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chemistry and high-throughput screening have significantly increased the number of compounds for which early data on absorption, distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.

ADMET in silico modelling: towards prediction paradise?

In the absence of effective vaccines to control herpesvirus infections, nucleosidic antiviral drugs have been the mainstay of clinical treatment since their development in the late 1970s. However, given the drawbacks of these drugs, including the increasing emergence of drug-resistant clinical isolates, new strategies for treating herpesvirus infections are warranted. A range of promising new drugs with novel molecular targets has been developed, but will they cure latent infections?

Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets

Supramolecular chemistry has expanded dramatically in recent years both in terms of potential applications and in its relevance to analogous biological systems. The formation and function of supramolecular complexes occur through a multiplicity of often difficult to differentiate noncovalent forces. The aim of this Review is to describe the crucial interaction mechanisms in context, and thus classify the entire subject. In most cases, organic host-guest complexes have been selected as examples, but biologically relevant problems are also considered. An understanding and quantification of intermolecular interactions is of importance both for the rational planning of new supramolecular systems, including intelligent materials, as well as for developing new biologically active agents.

Binding Mechanisms in Supramolecular Complexes

Property-based design: optimization of drug absorption and pharmacokinetics.

Calculated molecular properties from 3D molecular fields of interaction energies have become a valuable approach to correlate 3D molecular structures with physicochemical and pharmacodynamic properties. In contrast, their use in correlations with pharmacokinetic properties is still poorly explored and exploited. 3D molecular fields can be obtained from ab initio, semiempirical or molecular mechanics levels of calculation. The newly developed procedure called VolSurf is able to compress the relevant information present in 3D maps into a few descriptors characterised by the simplicity of their use and interpretation. These descriptors can be quantitatively compared and used to build multivariate models correlating 3D molecular structures with biological responses. The VolSurf procedure is applied here to generate descriptors and models of structure–permeation relationships. The VolSurf procedure, which was originally designed to handle a medium amount of data, can easily be applied to problems of large size such as bioisostere databases, CombyChem databases and related approaches.

Molecular fields in quantitative structure–permeation relationships: the VolSurf approach

Lipophilicity: the empirical tool and the fundamental objective - an introduction, V. Pliska, B. Testa and H. Van de Waterbemmd lipophilicity: a history, M.S. Tute thermodynamics of van der Waals and hydrophobic interactions, R. Zahradnik and P. Hobza intramolecular interactions encoded in lipophilicity: their nature and significance, B. Testa, P.-A. Carrupt, P. Gaillard and R.-S. Tsai lipophilicity measurement by reversed-phase high-performance liquid chromatography (RP-HPLC), H. van de Waterbeemd, M. Kansy, B. Wagner and H. Fischer centrifugal partition chromatography for lipophilicity measurements, R.-S. Tsai, G. Lisa, P.-A. Carrupt and B. Testa assessment of distribution-pH profiles, A. Avdeef estimation of lipophilicity by reversed-phase thin-layer chromatography, R. Mannhold, K. Dross and C. Sonntag the future of log P calculation, A.J. Leo theoretical calculation of partition coefficients, W.G. Richards cellular automata model of partitioning between liquid phases, L.B. Kier and C.-K. Cheng the molecular lipophilicity potential (MLP): a new tool for log P calculations and docking, and in comparative molecular field analysis (CoMFA), P.-A. Carrupt, et al hydrophobic fields in quantitative structure-activity relationships, G. Folkers and A. Merz physico-chemical and biological factors that influence a drug's cellular permeability by passive diffusion, R.A. Conradi, et al the role of lipophilicity in biological response to drugs and endogenous ligands, V. Pliska membrane transport and cellular distribution, S. Balaz applications of a solvation equation to drug transport properties, M.H. Abraham and H.S. Chadra environmental hazard assessment using lipophilicity data, R.L. Lipnick lipophilicity in peptide chemistry and peptide drug design, J.-L. Fauchere side chain lipophilicity of noncoded alpha-amino acids: pi-values the application of the intermolecular force model to bioactivity, peptide and protein quantitative structure-activity relationships, M. Charton lipophilicity descriptors for structure-property correlation studies: overview of experimental and theoretical methods and a benchmark of log " calculations, H. van de Waterbeemd and R. Mannhold.

Lipophilicity in drug action and toxicology

This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and (1)H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure-disposition and structure-activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments.

Liposome/water lipophilicity: methods, information content, and pharmaceutical applications.

Keywords:

molecular structure;
molecular properties;
fluctuation molecular states;
conformational behavior;
molecular fields;
lipophilicity;
molecular complexity;
solute-solvent interactions;
ligand-receptor interactions;
molecular recognition;
emergent properties;
dissolvence

A systems approach to molecular structure, intermolecular recognition, and emergence-dissolvence in medicinal research

Intramolecular Interactions Encoded in Lipophilicity: Their Nature and Significance

The electronic properties of orthopramides, a group of selective D-2 dopamine receptor antagonists, were investigated by calculating molecular electrostatic potentials (MEP) of model compounds with the ab initio STO-3G MO method. The various substitution patterns of the aromatic ring are characterized by a positive region comprising the H-bonded 2-methoxy group and ring positions 2, 3, and 4 and a negative region comprising the CONH group, 5-substituent, and ring positions 5 and 6. The regions of positive and negative potential are separated by a "curtain" running along the longitudinal axis of the molecule. At shorter distances from the plane of the aromatic ring (1.75 and 2.0 A), this "curtain" is quite sinuous, but at greater distances (2.5 and 3.0 A) it tends toward rectilinearity. We postulate that this longitudinal separation, together with the single positive maximum and the three negative minima perceptible at 3.0 A, constitute a distance pharmacophore responsible for the recognition and proper alignment of the ligand. The more complex MEP at 1.75 and 2.0 A are equated with a contact pharmacophore. Comparison of the MEP of orthopramides and dopamine reveals some analogies and suggests a possible mode of binding of these antagonists to the D-2 receptor.

Bernard Testa

Papers

Lipophilicity in drug action and toxicology

Liposome/water lipophilicity: methods, information content, and pharmaceutical applications.

A systems approach to molecular structure, intermolecular recognition, and emergence-dissolvence in medicinal research

Intramolecular Interactions Encoded in Lipophilicity: Their Nature and Significance

Molecular electrostatic potential of orthopramides: implications for their interaction with the D-2 dopamine receptor.