General characteristics of molecules
The two principal characteristics which control the interactions between drugs and biological molecules are their spatial structure and their electronic distribution.
The structure of a molecule is determined by its configuration and its conformation.
The spatial structure of a molecule, drug or endogenous compound, depends on the relative location of each atom in the molecule. This location depends itself on the number of electrons of valence, the orientation of their orbitals and on the interatomic distances. A molecule has only one configuration, i.e. a definite spatial arrangement of the atoms between each other in the molecule.
Isomerism is a characteristic of spatial structure of certain molecules, in particular those which have an asymmetrical carbon, i.e. a carbon bound to four different substituents. When the location of these four substituents is different in two molecules otherwise similar, they are called isomers.
These isomers, which are the image one of the other in a plane mirror, are comparable with a right hand and a left hand and are called chiral molecules. They are, by convention, named by the letters R (Rectus) and S (Sinister), according to the relative location of their substituents. One cannot pass from an isomer R to an isomer S without breaking the molecule to change the location of the substituents on the asymmetrical carbon.
When a drug is constituted of a mixture of two isomers S and R, it is called racemic or racemate. When it is constituted of only one isomer, R or S, it is known as pure enantiomer or enantiopure.
The isomers R and S can have similar, different or even antagonist properties. Among a lot of drugs having one or more asymmetrical carbons, one can quote beta-blockers, fenfluramine, fluoxetin, vitamin E. Probably, the new drugs will be, more and more often pure enantiomers.
There are also diastereoisomers, or geometrical isomers, according to the location of the substituents in relation to a rigid structure, double bond, or plan such as a cycle. They are named by the cis and trans terms. The cis and trans unsaturated fatty acids have different physicochemical and biological properties.
A molecule has only one configuration but it can, if it constituted of simple bonds, take various conformations because of the free rotation of the atoms around the simple bonds. To each conformation of a molecule corresponds a particular shape in space.
Each molecule has one or two privileged conformations induced by steric constraints of atoms and electrostatic interaction, repulsion or attraction between them.
The possibility of changing conformation gives to the molecules a flexibility enabling them to adapt ones to others. One speaks in this case of induced conformations. This conformational adaptability plays a determining role in the majority of the biologic phenomena.
Distribution of the electrons:
The polarity of a molecule results from the non homogeneous distribution of its electronic cloud.
Electron density, i.e. the distribution of the electrons in a molecule, is generally not uniform. The electrons accumulate around certain atoms which attract them and increase thus their negative charge, whereas other atoms repulse them and take a positive charge.
More the charge is localized in a small space, more it is reactive. Electron density of an ion is more important as its charge is high (1, 2, 3) and that its radius is little. An area with strong electron density of a molecule is called nucleophilic because it reacts preferentially with an area with weak electronic density of another molecule, called electrophilic.
Polarizability indicates not the electronic distribution in a molecule in the absence of external influence, but the facility with which its electronic cloud can be displaced under the effect of an electric field or of another molecule. In general, the polarizability of the atoms slightly charged and involving a great number of electrons is high. Thus the polarizability of the group HS is approximately three times higher than that of the group OH, the sulfur atom having sixteen electrons whereas oxygen has only eight. The polarizability of S is much higher than that of O.