Molecular fields to assess recognition forces and property spaces

Since the emergence of combinatorial chemistry and chemical libraries, great attention is being paid to the concepts of chemical diversity and chemical space. This approach is based on the assumption that molecular properties are invariant ones. But a growing computational power shows that a molecule cannot be considered as a static object but as an animated subject whose conformational changes may significantly affect the profile of any of its computable property. The ensemble of all conformers of a given compound is often taken as defining a conformational space. In a similar manner, many molecular properties can be shown to vary with the 3D-geometry of the molecule. In particular, powerful computational methods based on molecular fields now allow some physicochemical properties to be computed for each conformer, as discussed in the first part of the chapter. Such methods include MEPs (Molecular Electrostatic Potentials), MLPs (Molecular Lipophilicity Potentials), which allows to back-calculate a partition coefficient of a given conformer, and the recent MHBPs (Molecular Hydrogen-Bonding Potentials). A range of property values corresponding to all realistic conformations must be examined and taken into account. The range of these values defines a property space whose form and extent will depend on both the solute and the relevant environment. In a second part, the chapter focuses on the property spaces of the acetylcholine in a variety of polar and hydrophobic solvents. The effect of the solvent on the conformational behaviour of acetylcholine is analyzed together with the corresponding effects on the property spaces. Moreover, attention is being paid to the cross-correlation among the profiles of these spaces (both physicochemical and structural). These interrelations lead to a definition of the concept of molecular sensitivity which describes the ability of a molecule to modify its physicochemical properties as its geometry changes, as presented in the third part of the chapter. The receptor selectivity of alpha-adrenergic ligands offers an illustration of the interest and limits of molecular sensitivity and property space range in dynamic QSAR analyses