Medicinal Chemistry

A drug is a xenobiotic. Most drugs are lipid-soluble (non-ionized). Drugs can not be too hydrophobic, as they are transported by water. The average molecular weight of a drug is around 350. About 80% of drugs have a molecular weight < 450, and about 11% > 500. The solubility are controlled by molecular weights of < 500. To cross cell membranes, small hydrophilic molecules with a molecular weight of up to around 600, permeate membranes through aqueous pores, whereas hydrophobic molecules diffuse across the lipid domains of membranes. The blood-brain barrier blocks drugs greater than 450 to 500 in molecular weight. Higher molecular weights typically mean more rotable bonds. If there is more functional groups, then therefore more hydrogen-bonding interactions.

Note, the above paragraph drug stats came out in early 2012, the next paragraph drug stats came out in late 2023.

About 84% of small-molecule pharmaceutical drugs contain at least 1 nitrogen, in which the average drug is ~2.3% N/drug. About 26% contain a least 1 sulfur, and 13% contain at least 1 fluorine. About %76 of oncology drugs contain a nitrogen. Of over 285 FDA-approved drugs containing at least 1 sulfur, sulfonamides make up 25% (72 drugs), sulfoxides about 4% (11 drugs), and sulfone about 3% (8 drugs). Nobody makes drugs containing sulfoximines because of an explosion hazard.

Most drugs are either weak acids or weak bases (both hydrophilic). (If they were weak oxidizing or weak reducing agents, they would affect mitochondria.). The stomach is acidic and the intestines are alkaline, so enteric-coated drugs allow drugs to bypass the stomach to be absorbed by the upper intestines. Drugs taken as pills or capsules are mostly absorbed in the upper intestine. An uncharged drug (lipophilic) can pass through the cell membrane and blood-brain barrier more easily, whereas hydrophilic chemicals are not.

Polar drugs are usually poorly absorbed and have to be administered by injection. They can be absorbed into the blood supply if they have a low molecular weight (about < 200), as they can pass through small pores between the cells lining the gut wall. The more polar the drug, the less likely it will cross the blood-brain barrier. The cells lining the blood-brain barrier do not contain pores (unlike capillaries elsewhere in the body).

About 80% of drugs are enzyme inhibitors. Enzymes speed up reactions by lowering the activation energy.

About 25% to 33% of alcohol is absorbed into the blood supply from the stomach, the rest are absorbed from the upper intestine. About 75% of an orally administered drug is absorbed into the body within 1 to 3 hours.

Most drugs do not have a nitrogen-nitrogen (single or double) or oxygen-oxygen bond. They fall under the category of reactive nitrogen species and reactive oxygen species. Most drugs also do not have a nitro group (-NO₂ substituent).

Drug targets.

The majority of drugs used in medicine are targeted to proteins, such as receptors, enzymes, and transport proteins (found in the cell membranes). Enzymes and receptors are the most important drug targets in medicinal chemistry. Receptors are identified by the specific neurotransmitter or hormone, which activates them. So, the receptor activated by adrenaline, and noradrenaline, are called the adrenergic receptor and adrenoreceptor. However, not all receptors activated by the same chemical messenger are exactly the same throughout the body. For example, the adrenergic receptors in the lungs are slightly different than the ones in the heart, in which the differences arise from slight variations in amino acid composition. Now, if the variations are in the binding site, then this allows for selectivity: medicinal chemists can design adrenergic drugs to be lung or heart selective. Drugs that block receptors are called antagonists.

The toxicity of poisons, toxins, and heavy metals, result from their action on enzymes. Some of the most famous enzymes in our body are the cytochrome P450 enzyme, and MAO (monoamine oxidase).

Structure-activity relationships (SAR).

Once a drug is designed, the medicinal chemist moves on to study its structure-activity relationships. If it is possible to crystallize the target with the drug bound to the binding site, the crystal structure of the complex could be solved by X-ray crystallography, then studied with a molecular modeling software to identify important binding interactions. But if this is not possible because the target structure has not been identified, or cannot be crystallized, it is then necessary to revert to the traditional method of synthesizing a selected number of compounds almost identical to the original structure, then studying what effect that has on the biological activity.

Examples of drug-design:

Substituents of aromatic rings.

-Whether a substituent is in the ortho, para, or meta position, of an aromatic ring, plays a role. For example, the electron-withdrawing nitro group will affect the basicity of an aromatic amine more slightly if it is in the para position than in the meta position. At the para position, it will make the amine a weaker base, and less likely to protonate. This would decrease the amine's ability to interact with ionic binding groups in the binding site, and therefore decrease activity.
-For electron-donating groups, will make a stronger base if it's in the ortho or para positions than in the meta position.
-Another way to improve activity, is by having a more electron-withdrawing substituent, such as replacing a methyl substituent with a chloro substituent.

Other examples.

-Just because 2 different substituents on a compound can be low activity when used by itself, does not mean they are low activity if both substituents are used at the same time. Such is the case for an earlier design of the anti-cancer drug sorafenib. It was shown to be slow activity with a phenoxy substituent, and with a isoxazole ring, when bonded to urea that was bonded to a paramethylbenzene. But when both were bonded to it at the same time, showed an increase in activity.

This whole thing is called QSARs (quantitative structure-activity studies). Measuring the activity, is in μM, for IC50. For example, 1.7 μM is 10x faster than 17 μM.

Company case study: AbbVie.

Abbott Labs split off into 2 companies, with AbbVie being the pharmaceutical company, in 2012. AbbVie has an advanced chemistry technology group, which formed in 2007 (which does flow chemistry, photo(redox) chemistry, and biocatalysis, etc.). However, their parallel library synthesis started in 2011. Their high-throughput experimentation started in 2017, which includes a proprietary chemistry-beads technology, of chemical-coated glass beads. ChemBeads was their solution to address miniaturized parallel screening needed. It enabled Suzuki-coupling optimization.

News release 11/12/2023.

Researchers say they've located a "kill switch" that can trigger the death of cancer cells. Scientists at the UC Davis Comprehensive Cancer Center in Sacramento, California, have identified a protein on the CD95 receptor that can "program" cancer cells to die, as detailed in a study published in the journal Cell Death & Differentiation last month.