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Hits and leads and drugs all bind to their protein targets. These interactions between these two are run by intermolecular forces and are responsible for the potency of the hit, lead, or drug. What is the nature of these interactions? Well, they're intermolecular forces, and they're really lots of different intermolecular forces. We're going to talk about just two -- hydrogen bonding and hydrophobic contacts. Hydrogen bonds require a hydrogen bond donor and a hydrogen bond acceptor. Normally hydrogen bond donors are O-H and N-H groups. You need both those atoms. And hydrogen bond acceptors are just the lone pairs on an oxygen or a nitrogen atom. A single hydrogen bond is worth anywhere from about 1 to 4 kcals/mol toward the binding energy. Hydrogen bonds between neutral hydrogen bond donors and acceptors, like an alcohol O-H and a neutral ketone oxygen tend to be weaker at about 1-2 kcals/mole. The energy of the hydrogen bond becomes stronger if either the donor or acceptor is charged. Charged donors are often protonated amines, which are basic enough to be protonated at a biological pH of 7.4. Charged acceptors are often carboxylic acids, which are acidic enough to be deprotonated at biological pH. The strongest hydrogen bonds arise if both the donor and acceptor are charged. So, in this case, it's about 4 kcal/mol. The energy of this intermolecular force is a combination of a hydrogen bond and electrostatic attraction between the opposite charges. Hydrophobic contact forces occur mostly between weakly polarized parts of the drug and target binding pockets of enzymes and receptors often contain non-polar or hydrophobic regions. Non-polar groups of a drug molecule interact well with this pocket. The weakly polarized groups include hydrocarbon chains and halogen atoms. The strength of the attractive forces are proportional to the surface area of contact between the two molecules and is approximately 0.03 kcals/mol/A^2 of interaction. For comparison, contact forces for a CH2 group might be 0.8 kcal/mol. A phenyl group or benzene ring my may generate 2.0 kcal/mol. Improving a molecule's potency involves reducing its IC50 or EC50, Ki or Kd. Ideally down below about 10 nM. How do we accomplish that task? Well, we add groups to the molecule to create new intermolecular forces between the drug and its protein target, whether those are hydrogen bonds or hydrophobic contact forces. This increases the affinity between the two molecules and increases potency. These intramolecular forces make the DeltaG more negative, more favorable. Ideally structural information like x-ray crystallographic data can inform the chemists on how to modify a molecule's structure to maximize intermolecular forces and potency.