Lecture 7: drug binding interactions III

Van der Waals interactions include

three types of interactions: Keesom forces, Debye forces, and London dispersion forces

Van der Waals interactions

weak, noncovalent attractions between atoms or molecules that are extremely close together

Debye forces

occur between a permanent dipole and an induced dipole

London dispersion

occur between two induced dipoles

induced dipoles

temporary separation of positive and negative charges in a normally nonpolar atom or molecule

dipole-induced dipole bond

one group is already polar, while the other becomes temporarily polarized because of the nearby permanent dipole

ability to form van der Waals interactions

highly dependent on the distance between the participating functional groups

drugs with long alkyl chains or aromatic rings

can form many van der Waals interactions, each interaction is weak but combined can be stronger

Hydrophobic bonding

when two nonpolar (water-fearing) groups come together in water, causing surrounding water molecules to be released

entropy increased

by hydrophobic interactions

Hydrophobic groups approach

Water is squeezed out → Entropy increases → Binding becomes more favorable

advantages of hydrophobic bonding

least sterically hindered, have the most conformational flexibility, and have the ability to be located in a nonpolar region of the biological target’s binding site

Chelation

when two distinct electron donating groups, present on the same molecule, bind to a metal ion and form a ring structure

Chelation therapy

important for Wilson’s disease, a genetic disorder resulting in inappropriate copper transport and the accumulation of copper in the liver, brain, kidneys, and the eyes

Copper accumulation

leads to tissue damage and prevents the affected organs from functioning normally

Most chelates involve

oxygen, nitrogen, and/or sulfur atoms that are present within the functional groups of a drug molecule

-form five- or six-membered rings

Tetracycline

an antibiotic, also works via chelation

solubility of chelates

very poor water solubility, hence, their formation will significantly decrease the absorption of tetracyclines

metal complexation

when a metal ion interacts with a single atom, however in this case the metal ion does not form a ring

ethylenediaminetetraacetic acid (EDTA)

compound that is used for the treatment of lead toxicity, hypercalcemia, and cardiac glycoside induced arrhythmias

Penicillamine and trientine

can chelate copper, increase its elimination in urine, and restore copper levels to normal values

Zileuton

anti-asthmatic drug that acts via chelation by inhibiting the enzyme 5-lipoxygenase and prevents the formation of inflammatory leukotrienes

β-dicarbonyl group of tetracycline

can form chelates with calcium, magnesium, aluminum, and iron in the GI tract

Angiotensin converting enzyme (ACE)

zinc protease that catalyzes the conversion of angiotensin-I to angiotensin-II, which is responsible for an increase in the blood pressure