symbiont.The presence of water profoundly influences the shape and function of all other
molecules and macromolecules within the body. Water is the solvent that bathes all mol-
ecular events. It is essential in determining the acid–base properties of all biomolecular
processes. Water lines all receptor sites, and an incoming drug must either incorporate
the water into the receptor binding process or displace it.
8.1.2 Amino Acids, Peptides, and ProteinsUnlike water, amino acids and peptides have been exploited as drug design targets for
many years. Amino acids, as implied by their name, are difunctional molecules: they
possess a basic amino group and an acidic carboxyl group. Arising from this difunc-
tional structure, amino acids are said to be amphoteric, since they can react as either
acids or bases. Moreover, amino acids can undergo an intramolecular acid–base reac-
tion and exist primarily in the form of a dipolar ion or zwitterion. The most important
amino acids, both structurally and functionally, are the α-amino acids, which have a
single carbon atom (the “α-carbon”) separating the amino group from the carboxyl
group. (β-Amino acids have two carbons separating the amino and carboxyl groups,
whileγ-amino acids have a three-carbon separation.)
8.1.2.1 Amino Acids, Peptides, and Proteins: Molecular Structure
There are twenty naturally occurring α-amino acids; 19 of them are primary amines, dif-
ferentiated only by the side-chain substituent appended to the α-carbon (see figure 8.1).
Proline is a secondary amine whose nitrogen and α-carbon atoms are part of a five-mem-
bered pyrrolidine ring. With the exception of glycine, the α-carbons of the amino acids
are stereogenic centers of chirality. α-Amino acids are fundamental building blocks that
can join together into long chains by forming amide bonds between the amino terminus
of one amino acid and the carboxyl terminus of another. The long repetitive sequence of
–N-CH-C(=O)- units that form the chain is called the protein backbone. The side-chains
of each amino acid then bristle away from this backbone structure. The various amino
acids that constitute the chain are referred to as residues. Chains with fewer than fifty
amino acids are peptides, while those with more than fifty are proteins.
Peptide and protein chains twist and turn upon themselves, producing elaborate and
complex structures that enable bioactivity. Primary structurerefers to the amino acid
sequence of the protein; secondary structure(consisting of α-helices,β-sheets,and
β-turns) describes how segments of the protein backbone orient into regular patterns via
intramolecular hydrogen bonding along the backbone; tertiary structuredescribes how
the entire protein molecule coils into a three-dimensional shape by means of multiple
intramolecular interactions involving both backbone and side-chain atoms; quaternary
structurerefers to the process whereby many individual protein molecules come together,
through various intermolecular interactions, to form a larger aggregate structure.
8.1.2.2 Types of Proteins
Proteins may be structural, functional, or catalytic. Structural proteins are frequently
fibrous proteins (insoluble polypeptide chains arranged side by side in long filaments)
466 MEDICINAL CHEMISTRY