**2.1.2 Van der Waals forces**

766 Thermodynamics – Interaction Studies – Solids, Liquids and Gases

need to determine the stoichiometry of the studied system to calculate accurately the constants. Once the thermodynamic concepts were introduced, we will show the use of these kind of studies for the optimization of drug binding to its target. We will detail the role of single chemical modifications in the molecule of study to modulate its binding affinity, and the way to quantify these changes. We will finally further discuss how the

Non-covalent interactions are chemical bonds that do not involve sharing of electron pairs between orbitals of different atoms, there are no orbital overlapping in these interactions which have an electrostatic nature and are not highly directional. Covalent bonds are generally shorter than 2Å while the non-covalent ones are within the range of several angstroms. Another difference between these two types of bonds is the energy released in its formation, non-covalent interactions are weaker, with energies below 40 kJ/mol whereas

These weak interactions have important roles in the binding of macromolecules with each other and with other molecules in the cell, in the mainteinance of the three dimensional structure of large macromolecules such as proteins or nucleic acids (e.g. DNA double helix) and they are the forces found in the majority of the drug-proteins interactions in

There are four commonly mentioned fundamental non-covalent interaction types including ionic interactions, hydrogen bonds, hydrophobic interactions and van der Waals forces (dispersion attractions, dipole-dipole and dipole-induced dipole interactions). All these weak interactions must work together to have significant effects. Their combined bond effect is greater than the sum of the individual ones. The free energy of multiple bonds between two molecules is different than the sum of the enthalpies of each bond due to entropic effects.

Ionic bonds result from the electrostatic attraction between two ionized groups of opposite charge such as carboxyl (-COO-) and amino (-NH3+). These ionic interactions are directly proportional to the product of the interacting charges and inversely proportional to the dielectric constant of the medium and the distance separating the charges. This relationship

E = kq1q2

where E is the energy, q1 and q2 are the charges of two atoms, r is the distance between them, D is the dielectric constant, and k is a proportionality constant. A charged group on a molecule can attract an oppositely charged group from another molecule. By contract, an attractive interaction has a negative energy. The dielectric constant is important for the medium. In water, these bonds are very weak as the dielectric constant is much higher (D=80) than in vacuum (D=1). As an example, the electrostatic interaction between two atoms bearing single opposite charges separated by 3 Å in water has an energy of 5.9 kJ/mol

Dr (1)

selection of the best sustituents can result in the optimization of binding.

**2. Non-covalent interactions** 

pharmacology.

**2.1.1 Ionic interactions** 

is defined by Coulomb's law:

(k=1389 kJ/mol).

covalent bonds energies range 80-800 kJ/mol.

**2.1 Types of non-covalent interactions** 

Van der Waals forces are short range attractive forces between chemical groups in contact. The forces are caused by slight charge displacements. The distribution of electronic charge around an atom changes with time. At any moment, the charge distribution is not perfectly symmetric. This transient asymmetry in the electronic charge around an atom induces a complementary asymmetry in the electron distribution around its neighboring atoms. These induced dipole effects give rise to the so called van der Waals interactions, also known as dispersion forces. The attraction between two atoms increases as they come closer to each other, until they are separated by the so called van der Waals contact distance. At a shorter distance, very strong repulsive forces become dominant because the outer electron clouds overlap. The van der Waals radius of an atom is defined where the net force between two atoms is zero. The van der Waals potential is then best described as a balance between attraction and repulsion.

Van der Waals forces are non-directional. Energies associated with them are quite small; typical interactions contribute from 2 to 4 kJ/mol per atom pair. However, when the surfaces of two large molecules come together, a large number of atoms are in van der Waals contact, and the net effect, summed over many atom pairs, can be substantial.
