Question

Knowing the quaternary structure of proteins, specifically their surface properties, provides novel opportunities for enhancing the development of targeted drug therapies. (a) Referring to Figure \(14-16\) and the accompanying discussion, predict the class(es) of amino acids likely to reside on the surface of a protein within a cell. (b) Assuming that Glu, Arg, and Asp exist in a functional site of a receptor molecule on the surface of a cell, provide an amino acid sequence that is likely to be effective in blocking that site. (c) The androgen receptor associated with prostate cancer has recently been targeted using synthetic molecules known generally as peptidomimetics, many of which incorporate D-amino acid stereoisomers rather than the more naturally occurring L-amino acid stereoisomers. Why might \(\mathrm{D}\) -amino acid stereoisomers be especially useful for inhibiting a functional site of the androgen receptor, or any deleterious functional site for that matter? (d) Rational drug design is a relatively recent approach to the design of targeted therapeutic agents. Predict how knowledge of protein structure, especially surface properties, might be used in rational drug design as compared with the more classical "trial-and-error" approach.

Short answer

Answer: Polar and charged amino acids, such as Serine (Ser, S), Threonine (Thr, T), Asparagine (Asn, N), Glutamine (Gln, Q), Aspartate (Asp, D), Glutamate (Glu, E), Lysine (Lys, K), Arginine (Arg, R), and Histidine (His, H), are likely to be found on the surface of a protein within a cell. This information can be used in rational drug design by identifying specific amino acids or protein regions that can be targeted by drugs. Understanding the protein's surface properties and active site enables researchers to design drugs with high binding affinity and specificity for the target protein, leading to a more efficient and potentially less time-consuming approach compared to random molecule screening.

Step-by-step solution

(a) Predicting Amino Acids on Protein Surface

According to Figure 14-16, the amino acids on the surface of a protein within a cell would primarily be polar and charged due to the polar nature of the cellular environment. Examples of these amino acids include Serine (Ser, S), Threonine (Thr, T), Asparagine (Asn, N), Glutamine (Gln, Q), and charged amino acids such as Aspartate (Asp, D), Glutamate (Glu, E), Lysine (Lys, K), Arginine (Arg, R), and Histidine (His, H).

(b) Suggesting an Amino Acid Sequence for Blocking the Site

The receptor molecule contains negatively charged Glu (E) and Asp (D), along with positively charged Arg (R). To effectively block the functional site, we need an amino acid sequence that has complementary charges. For Glu and Asp, we can use positively charged amino acids such as Lysine (K) or Arginine (R). Conversely, for Arg, we can use negatively charged amino acids such as Aspartate (D) or Glutamate (E). A possible sequence could be KDKE or REDE.

(c) Advantages of D-Amino Acid Stereoisomers

D-amino acid stereoisomers could be advantageous for inhibiting functional sites because they are less prone to being degraded by proteases, as proteases typically recognize and cleave L-amino acid residues. This could lead to longer-persistence of D-amino-acid-containing drugs within the body and potentially more effective targeting of the receptor site.

(d) Using Protein Structure Knowledge in Rational Drug Design

In rational drug design, knowledge of protein structure, especially surface properties, can help researchers identify specific amino acids or protein regions that can be targeted by drugs. By understanding the protein's active site, its interaction with other molecules, and its physicochemical properties, researchers can design drugs that have high binding affinity and specificity for the target protein. This focused approach is more efficient and potentially less time-consuming compared to the "trial-and-error" method, which involves the random screening of thousands of molecules to identify potential drug targets.

Key concepts

Amino Acid Properties

Amino acids are the building blocks of proteins. Their properties determine the structure and function of the proteins they compose. In an aqueous cellular environment, polar and charged amino acids are more likely to be found on the protein surface, where they can interact with water molecules and other cellular substances.

Charged amino acids like Aspartate (Asp), Glutamate (Glu), Lysine (Lys), Arginine (Arg), and Histidine (His) contribute to the protein's interaction with its environment through ionic bonds and electrostatic attraction. Neutral polar amino acids such as Serine (Ser), Threonine (Thr), Asparagine (Asn), and Glutamine (Gln) form hydrogen bonds with water or other polar substances. This understanding is crucial when predicting protein interactions and designing inhibitors, like in the solutions proposed for blocking functional sites on cell surface receptors.

Rational Drug Design

Rational drug design is a methodical approach to creating therapeutic agents. This process involves understanding the intricate details of the target protein's structure, particularly the role of its surface properties in disease mechanisms. Unlike traditional methods that rely on serendipity, rational drug design accelerates the discovery of effective drugs by focusing on the molecular level.

Researchers use computer modeling to visualize protein surfaces, identify key binding sites, and understand the dynamic interactions with potential drug molecules. By knowing which areas of the protein to target and what structural features the drug must have, scientists can craft molecules that fit like a key in a lock, enhancing the drug's efficacy and reducing unwanted side effects.

Peptidomimetics

Peptidomimetics are molecules that mimic the structure of peptides but have been modified to enhance their drug-like properties. They play a pivotal role in therapeutic development, especially when peptides themselves would be unsuitable as drugs due to rapid degradation by proteases.

By incorporating D-amino acid stereoisomers, peptidomimetics gain resistance to enzymatic breakdown, resulting in a longer duration of action in the body. Since most natural peptides are composed of L-amino acids, using D-amino acids can create novel structures that retain the ability to bind targets with high affinity while evading proteolytic cleavage, making them exceptionally useful in designing inhibitors for specific proteins like the androgen receptor in prostate cancer.

Protein Surface Properties

The surface properties of a protein are essential in mediating its interactions with other biomolecules, ions, and the surrounding environment. These properties include hydrophobicity, charge distribution, and the presence of specific chemical groups that can form bonds.

Understanding these protein surface characteristics allows for the strategic design of inhibitors that can bind to particular functional sites. In drug design, knowledge of these surface interactions is leveraged to create molecules that effectively compete with natural ligands or substrates, thereby modulating the protein's activity. The exact mapping of surface properties also aids in predicting how alterations to the protein, whether through mutation or chemical modification, could affect drug binding and function.