Medicinal Chemistry — Understanding Drug Targets

This section will go over drug targets in biological systems from a medicinal chemistry perspective. The purpose of this section is to give an overview of the molecular structures of major macromolecular targets in the body.

The main drug targets in the body are normally large molecules. Macromolecule is the word used to describe large molecules with high molecular weights. These large molecules are made up of smaller subunits. Examples of macromolecules include proteins and nucleic acids. Knowing the functional groups and structural features of the macromolecules can provide an insight on the possible interactions that can take place between the drug and its target at the binding site. Armed with this knowledge, medicinal chemists can introduce structural modifications to a lead compound and optimise drug-target interactions.


Amino Acids

Most drugs in clinical use target proteins such as receptors, proteinaceous enzymes, transport proteins, membrane proteins, and ion channels. Understanding the chemistry of proteins is important in drug design. In humans, proteins are typically composed of a set of 20 standard amino acids. This class of organic compounds are made up of a carboxylic acid functional group, a side chain characteristic of that amino acid, and an amine functional group. The generic structure of the unionised α-amino acid is shown below.

α-amino acid

The presence of the carboxylic acid and amine functional groups give amino acids their amphiprotic properties. In solution, amino acids exist as an equilibrium mixture of neutral species and zwitterions. Approximately 500 amino acids are known. As mentioned earlier, 20 amino acids are commonly found in humans. The information regarding the standard 20 amino acids found in humans are tabulated below.

Amino Acids with Hydrophobic Side Chains

Amino Acids with Hydrophobic Side Chains

Amino Acids with Hydrophobic & Aromatic Side Chains

Amino Acids with Hydrophobic & Aromatic Side Chains

Amino Acids with Uncharged Polar Side Chains

Amino Acids with Uncharged Polar Side Chains

Amino Acids with Cationic Side Chains

Amino Acids with Cationic Side Chains

Amino Acids with Anionic Side Chains

Amino Acids with Anionic Side Chains

Other Amino Acids

Other Amino Acids

Drugs interact with proteins by establishing noncovalent or covalent bonds. The different side chains of amino acids can participate in intermolecular interactions with a drug. For instance, a drug with an aromatic group can have π-π interactions with a Phe residue at a receptor’s binding site. Given the structures of the amino acids, can you come up with other possible noncovalent drug-target intermolecular interactions?

Some of these amino acids are biosynthesised in the body and some of them are not. Amino acids that cannot be synthesised in the body and must be acquired through one’s diet are called essential amino acids. The amino acids that humans cannot biosynthesise are arginine (conditionally essential), histidine, isoleucine, leucine, threonine, lysine, methionine, phenylalanine, tryptophan and valine. One way of remembering the essential amino acids is using the phrase:

Any Help In Learning These Little Molecules Proves Truly Valuable”.

All 20 amino acids apart from glycine contain a chiral carbon atom at the carbon in the α-position (Ca). Most amino acids found in nature are L-amino acids. D-amino acids are much rarer and are found in places such as the bacterial cell wall. Proteins are made up of amino acids linked together through peptide bonds (amide bond). The peptide bond is a covalent bond formed between the amine of one amino acid and the carboxylic acid of another to form an amide and water. Peptide bond formation is a condensation reaction. Bond rotation about the peptide bond is hindered. The planar nature of the peptide bond imposes restrictions on the conformations proteins can adopt. On the other hand, there is free rotation about the Ca-N and Ca-C bonds.

Peptide Bonds

The majority of proteins contain 50 – 2000 amino acids. Protein structure is divided into four levels – primary, secondary, tertiary, and quaternary. Proteins can also undergo post-translational modifications.

Levels of Protein Structure

Primary Structure

The linear sequence of amino acids which are linked through peptide bonds is known as the primary structure. Disulfide bonds between cysteine residues are also included in the primary structure. The resulting disulfide compound is formed through an oxidation reaction between two cysteine molecules. The amino acid product of the reaction is called a cystine residue (without the e).

Secondary Structure

The secondary structure refers to the regular folding of certain regions of the polypeptide. α-helices and β-pleated sheets are two of the most common types of secondary structures.

The α-helix results from the coiling of the peptide chain. The coiling is maintained by the formation of intramolecular hydrogen bonds that are directed parallel to the helix axis. Amino acids essentially lie perpendicularly from the helix, minimising steric interactions, thereby granting the structure more stability. G-protein coupled receptors (GPCRs) are important drug targets. GPCRs contain several transmembrane α-helices.

In β-pleated sheets, hydrogen bond formation occurs between adjacent sections of the polypeptide that run in the opposite direction (antiparallel) or in the same direction (parallel). Again, to minimise steric interactions, residues lie perpendicularly to the sheets.

Tertiary Structure

The tertiary structure refers to a protein’s three-dimensional arrangement in space. Excluding disulfide bonds, the native, biologically active conformation is stabilised by noncovalent intramolecular interactions such as ion-dipole interactions. Proteins are said to undergo folding when assuming its functional shape. The three-dimensional structure of proteins is crucial to their biological function. When drugs bind to proteins, the protein undergoes conformational change. A change in conformation usually means altered function. The tertiary structure is of great importance during drug design. During computer-aided drug design, the 3D structure of proteins can be used to study binding interactions through computational chemistry and molecular modelling software packages.

Quaternary Structure

In cases where a protein is made up of more than one polypeptide chain, the quaternary structure refers to the spatial arrangement of more than one different polypeptide chains and the interactions established between them. For example, haemoglobin is composed of four subunits – two identical alpha units and two identical beta subunits. Haemoglobin is said to have a quaternary structure.

Proteins are ubiquitous in living organisms, making up receptors and ion channels as well as playing roles in enzyme catalysis. It is easy to see why proteins are the main targets of drugs in clinical use. For example, HMG-CoA reductase is an enzyme involved in the biosynthesis of cholesterols. The enzyme is the drug target of the class of drugs known as statins. Examples of statins include pravastatin (Pravachol) and atorvastatin (Lipitor).


Nucleic Acids

Nucleic acids are another class of important drug targets. They are of particular significance in the medicinal chemistry of certain anticancer drugs and gene silencing therapeutics. DNA and RNA are nucleic acids. Just like proteins, nucleic acids are polymeric macromolecules. The monomeric units of nucleic acids are referred to as nucleotides.

Nucleotides are made up of at least one phosphate group, a pentose (5-carbon sugar), and a heterocyclic nitrogenous base (referred to as nucleobases). For DNA, the pentose is deoxyribose whereas for RNA, the pentose is ribose. The nucleobases are adenine, thymine, guanine, cytosine, and uracil (RNA). The nucleobases are further divided into purines and pyrimidines. When the nucleobase is covalently bonded to the pentose alone, it is referred to as a nucleoside. Structures and the numbering system are shown in the image below. To summarise:

  • Nucleobase: Nucleobase alone
  • Nucleoside: Nucleobase + Pentose
  • Nucleotide: Nucleobase + Pentose + Phosphate(s)
  • Nucleic Acid: Polymerisation of nucleotides. Nucleotides are linked through 3’-5’ phosphodiester linkages











The names of the ribonucleosides are adenosine, guanosine, uridine, and cytidine. Given the structures of ribose and the nucleobases found in RNA, can you draw the ribonucleobases?

Nucleobase & Pentose Numbering System

Nucleobase & Pentose Numbering System

Can you draw the rest of the nucleotides?

The 3’-5’ Phosphodiester Linkage

Highlighted in blue

3’-5’ Phosphodiester Linkage

Each nucleotide making up the nucleic acid can be thought of as a single letter making up a nucleic acid alphabet. The four letters of the ‘DNA alphabet’ are A, T, G and C, standing for adenine, thymine, guanine, and cytosine.  By convention, the sequence of nucleotides is written in the 5’ ? 3’ direction. In RNA, T is replaced by U (for Uracil).

Most DNA molecules are made up of two complimentary polynucleotide strands that coil around each other to form a double helix. The double helix of the DNA is stabilised by specific hydrogen bonding interactions between the nucleotides, and mainly by π-π stacking interactions. The specific hydrogen bonding between pairs of nucleobases often found in the DNA double helix is referred to as base pairs. These are:

  • Adenine ↔ Thymine
  • Guanine ↔ Cytosine

This base-pairing is sometimes referred to as Watson-Crick base pairing. One way of remembering Watson-Crick pairing is by using the phrase ‘At The Giant’s Causeway’. The Giant's Causeway is an area of basalt columns found in Northern Ireland.

The human genome is made up of approximately 3 billion base pairs of DNA.  Other modes of base-pairing are known, such as Hoogsteen base pairing. RNA exhibits non-canonical base pairing more so than DNA.

Watson-Crick Base Pairing

The most common form of DNA is known as B-DNA. Other forms of DNA such as A-DNA and Z-DNA are also known.  The double strand of DNA possesses features known as grooves. The wider groove is known as the major groove (~11.6 Å wide) whereas the narrower groove is known as the minor groove (~6 Å wide). The grooves of B-DNA possess a well-defined spine of hydration. Both the major and minor grooves can serve as binding sites for drugs.

DNA essentially carries the genetic information of an organism. Interfering with DNA can be detrimental to a cell. The drugs that interact with DNA can be grouped into:

  • Groove Binders
  • Intercalators
  • Alkylating Agents
  • Chain Terminators
  • Chain Cutters

Groove Binders

Groove binders are further divided up into minor groove binders and major groove binders. Major groove binders tend to be large molecules like oligopeptides and oligonucleotides. Minor groove binders tend to be flexible, can establish hydrogen bonds with DNA, and tend to be polyamines. An example would be the anticancer agent, distamycin.



Intercalators tend to be cationic, aromatic, planar polycyclic systems with the ability to interact with DNA through noncovalent π-π interactions. Recall that the DNA double helix is made up of aromatic ring systems and a negatively charged sugar-phosphate backbone. The cationic group of intercalators may interact with the anionic sugar-phosphate backbone through ionic interactions. Intercalators can unwind and lengthen DNA molecules. Intercalators tend to be antitumour or antibacterial drugs.

The structure of the antibacterial compound proflavine, is shown below. It fits the criteria of an intercalator described above. The charged form of the drug intercalates with DNA. The planar acridine interacts with bacterial DNA through π-π interactions. The quaternary ammonium cations interact with the anionic sugar-phosphate backbone through ionic interactions. Proflavine is a bacteriostatic compound that was used during the First and Second World wars to treat deep surface wounds.


Alkylating Agents

As the name suggests, alkylating agents form covalent bonds with DNA. Alkylating agents tend to be highly electrophilic and react with nucleophilic groups of DNA. The nucleophilic groups of DNA are:

  • Adenine: N1, N3
  • Guanine: N7
  • Cytosine: N3

It is also possible for nucleophilic groups in proteins to react with alkylating agents, giving the class of drugs selectivity problems. Drugs that possess two electrophilic groups can react with the opposing strand of DNA causing crosslinking. Mustard gases used during the First World War are an example of alkylating agents. Lomustine, a compound employed in chemotherapy, is an example of a clinically used alkylating agent.


Chain Terminators

Chain terminators are drugs that incorporate themselves in DNA during replication and cease chain growth. They are structurally similar enough to DNA building blocks that the cell’s DNA replication machinery ‘mistakes’ them as authentic building blocks. Chain terminators are typically prodrugs which are triphosphorylated in the organism to give the active drug. Arguably the most important feature of chain terminators is that their structure restricts further addition of DNA building blocks to the growing DNA strand. An example of a chain terminator would be aciclovir. Aciclovir (or acyclovir) is a highly selective antiviral bioprecursor prodrug that is activated by phosphorylation in the organism. This drug is a guanosine analogue that is mainly used to treat herpes simplex virus infections.


Chain Cutters

Chain cutters are compounds that act on DNA through strand scission. Their mechanism of action appears to involve radical chemistry. An example of a chain cutter is the known antitumour compound, calicheamycin γ1. Calicheamicins are known to be synthesised by the bacterial species, micromonospora echinospora.

Calicheamycin γ1

Calicheamycin γ1
This concludes the article on drug targets from a medicinal chemistry perspective. Protein-protein interactions and biosynthetic building blocks may be targeted as well. Other drug targets include lipids and carbohydrates. However, the number of drugs that act on these targets is relatively small compared to drugs that target proteins and nucleic acids.

Further Reading

Drugs, their targets and the nature and number of drug targets:

  • Nature Reviews Drug Discovery, 2006, 5, pp 821-834.

The Druggable Genome

  • Nature Reviews Drug Discovery, 2002, 1, pp 727-730.

New Naturally Occurring Amino Acids

  • Angew. Chem. Int. Ed. Engl., 1983, 22 (22), pp 816–828.

How do drugs work?

By | 2015-11-24T15:53:03+00:00 December 2nd, 2014|Medicinal Chemistry|0 Comments

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