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There are many different types of intermolecular forces that you may remember from your days in general chemistry. All of these on the screen (and others) can play a role in target engagement by a molecule. Of the forces on this list, hydrogen bonding is particularly important. We’ll also detail another effect – hydrophobic contacts.
Hydrogen bonding involves two key players. First, you need a hydrogen-bond donor or HBD. This is normally an N-H or O-H group. Second, you need a hydrogen-bond acceptor, HBA. This is normally a nitrogen or oxygen atom with a lone pair of electrons. I have two diagrams of hydrogen bonding interactions at the bottom of the screen. To the left is an alcohol bonding to another alcohol. The hydrogen on one alcohol is interacting with the lone pair on the oxygen of the other alcohol. This type of hydrogen bond provides 1-to-2 kcal/mol of binding energy. To the right is another hydrogen bond. In this case, an anionic carboxylate oxygen is the HBA, and an ammonium ion N-H is the HBD. This interaction is a combination of a hydrogen bond and an ionic attraction and is therefore stronger at about 3-to-4 kcal/mol.
Hydrophobic contact forces involve minimizing the exposure of non-polar groups to water. The “force” is more related to entropy than an actual attractive force like hydrogen bonding. The yellow rounded rectangle in the cartoon is our drug. Drugs are normally non-polar. Water molecules form a fairly rigid, ordered cage – a solvent shell – around the drug to minimize contact between the non-polar surface of the drug and the polar water molecules. As we move to the right, the drug binds to its target and most of the water molecules are released to the surrounding medium. The release of water molecules increases the entropy of the system and favors binding. The amount of energy favoring binding is related to the surface area between the target and drug and is approximately 0.03 kcal/mol/Å2 of surface area.
Drug binding normally involves a combination of different forces. The binding of imatinib, a cancer drug, to its target involves multiple hydrogen bonds. One has the pyridine nitrogen as a hydrogen bond acceptor to an N-H hydrogen bond donor in the peptide backbone of the target. Another has an amide N-H in imatinib as the donor for a glutamic acid hydrogen bond acceptor. Hydrophobic contacts involve the pyridine… excuse me, pyrimidine ring of imatinib and the phenyl of a phenylalanine residue and the pyridine ring in the drug with the phenol ring of a tyrosine residue in the target. The binding energy of imatinib is 7… approximately 7 kcal/mol, and these individual interactions between imatinib and its target contribute to that total binding energy of 7 kcal/mol.