Consequences of the interaction
The interaction between two molecules can lead to the establishment of a connection between them. This connection can be strong, generally irreversible, with covalent bond or weaker, transient, with low energy interactions.
Covalent bond results from the sharing by two atoms of two electrons which bind them. To ensure this connection, electron orbitals of the two atoms overlap. This covering can be axial, the axis passing by the nuclei of the two atoms, forming a sigma bond, or lateral forming a pi bond such as existing in double and triple bond. In addition, the existence of electrons in antibonding orbitals weakens the covalent bond.
The energy of covalent bond lies between 30 and 100 Kcal/mol. This bond, taking into account its energy, is generally irreversible. This concept of irreversibility must be moderate: when a molecule has established a covalent bond with a molecule B to give a molecule AB the reaction can be regarded as irreversible. However if this molecule AB is put in the presence of a molecule C having a greater affinity for the molecule A, the equilibrium can be displaced towards the formation of a molecule AC. It is what is observed in reactions involving thiol groups, chelators, Schiff bases. Moreover, if the molecule AB is placed in a new environment different by the hydrogen ion concentration or the oxydoreduction potential, it can dissociate.
The number of drugs which directly establish covalent bonds with endogenous molecules is rather limited. One can quote among those, as examples, alkylating agents and platinum which bind DNA with which they constitute adducts, penicillin which binds PBP (penicillin binding proteins), aspirin which acetylates cyclooxygenases, a metabolite of omeprazole which binds the sulfur atom of cystein, an amino acid constitutive of the proton pump.
A certain number of adverse effects of drugs is explained by the formation of covalent bonds between drug or its metabolites and of the endogenous molecules.
The establishment and the rupture of covalent bonds play a capital part in the metabolism, biosynthesis, the biological breakdown of the endogenous products, the biotransformation of drugs and the effects which they initiate (activation of enzymes, phosphorylation etc). These transformations require energy, usually supplied by the hydrolysis of ATP, and the presence of enzymes which facilitate the biochemical reactions.
By inhibiting an enzyme, a drug can prevent the formation or the destruction of covalent bond.
Interactions of low energy
The molecular interactions of low energy, named Van der Vaals forces, include interactions between permanent dipoles (Keesom type), interactions between permanent dipoles and induced dipoles (Debye type) and the interactions between instantaneous dipoles ( London type). The energy of these electrostatic interactions of is about 0.5 to 1 Kcal/mol.
The endogenous molecules, in particular proteins, and many drugs are ionized in the biological media and there are between them attractive forces (charges of opposite sign) and repulsive forces (charges of the same sign).
Hydrogen bond is an interaction between a hydrogen atom, and another atom like oxygen, nitrogen, sulfur, either of the same molecule and the bond is intramolecular, or of two molecules and the bond is intermolecular. The energy of the hydrogen bond is approximately 5 Kcal/mol, sufficiently high to have important consequences and sufficiently low to be easily reversible. The hydrogen bond plays a considerable part in stabilization of proteins and nucleic acids, in the exchanges of protons and it explains the characteristics of the water molecule.
The hydrophobic Interactions result from the attraction and repulsion forces between molecules, polar molecules on one hand and nonpolar molecules on the other hand tending to be assembled between them. This interaction is at the origin of the separation of water and lipid phases. After an emulsion fatty acid/water, the oil droplets are assembled spontaneously between them and separated from water, reducing the surface area of the polar /non polar interface. The dimerization by formation of bonds called leucine zipper is an example of hydrophobic interaction.
Concept of hydration
In the biological media the polar molecules, especially those which are ionized, are surrounded by water molecules: the positively charged molecules interact with the oxygen atom of water and the molecules negatively charged with the hydrogen atom. It is admitted that when two hydrated molecules interact, they are at least partially transiently “dehydrated” at the time of their interaction.
These interactions of low energy exist for example between messengers and receptors and are generally reversible. The interactions which occur between a molecule and a receptor can be summarized as follows:
- They do not have any affinity one for the other and it does not occur anything at the end of a random meeting.
- Drug has a great affinity for a receptor because of their structural and electrostatic complementarities and they interact without inducing a modification of the receptor or by inducing a non functional modification. They are in this case antagonist because, due to affinity, they bind to the receptor and inhibit the binding of the agonist.
- Drug, not only binds the receptor, but also activates it, eliciting a series of enzymatic reactions at the origin of the effect observed. In this case, it is an agonist.
One does not know exactly how a messenger elicits, while binding to a receptor, the opening of a channel or a cascade of enzymatic reactions. But it is known that it induces conformational modifications, modifications of electronic distribution, exchange of protons or electrons. One finds in the literature specific studies concerning the mechanism of activation of receptors involving for example an exchange of protons, but not yet a general explanatory concept.
Whatever the type of binding, the effect of a drug depends on its target:
- if, for example, a drug interacts with an alfa-1 adrenergic receptor of a vascular fiber, either as agonist to stimulate it, or as antagonist to withdraw it from the influence of the endogenous agonist noradrenaline, the consequences of this interaction is a modification of the activity of the Gp proteins and phospholipase C and an increase in the intracellular calcium concentration and a vasoconstriction with the agonist and the opposed effect, a relaxation with the antagonist.
- if a drug inhibits an enzyme, the angiotensin converting enzyme, ACE, for example, an ACE inhibitor causes a diminution of the angiotensin II formation, a cholinesterase inhibitor causes an accumulation of acetylcholine, an inhibitor of the viral reverse transcriptase disturb the replication of the virus.
- If drug interacts with a channel of a membrane, the function of this channel will be modified.
These considerations explain the interest of the classification of drugs according to their targets.