7.8 Targeting Cell Nucleus Structures
The final nonmessenger cellular target for drug design is the cell nucleus—the storage
site for the cell’s hereditary information. The nucleus is surrounded by a double mem-
brane, the outer layer being from the endoplasmic reticulum and the inner layer from
the nucleus itself. Within the nucleus is the important organic acid, deoxyribonucleic
acid (DNA). Also in the nucleus is the nucleolus, which is largely composed of ribonucleic
acid (RNA).
The nucleic acids DNA and RNA are the chemical carriers of the cell’s genetic infor-
mation. Coded in a cell’s DNA is all of the information that determines the molecular
nature of that cell, that controls cell growth and division, and that directs the biosyn-
thesis of the enzymes and structural proteins required for all cellular functions. Not
surprisingly, nucleic acids represent potentially important targets in drug design. Nucleic
acids are biopolymers composed of nucleotides that are joined together to form a long
chain. Each nucleotide is constructed from a nucleoside bonded to a phosphate group;
each nucleoside is composed of an aldopentose sugar (2′-deoxyribose in DNA, ribose
in RNA) linked to either a heterocyclic purine or pyrimidine base. In DNA, there are
four different heterocyclic bases: two are substituted purines (adenine and guanine),
two are substituted pyrimidines (cytosine and thymine). In RNA, thymine is replaced
by uracil. In both DNA and RNA the heterocyclic base in bonded to the C1′atom of the
pentose sugar, while the phosphoric acid is bonded to the C5′sugar atom via a phos-
phate ester. Nucleotides join together in DNA and RNA by forming a phosphate ester
bond between the 5′-phosphate group on one nucleotide and the 3′-hydroxyl group on
the sugar of another nucleotide.
In 1953, Watson and Crick made their Nobel Prize winning proposal concerning the
secondary structure of DNA. DNA consists of two polynucleotide strands coiled around
each other in a double helix. These two complementary strands run in opposite direc-
tions and are held together by hydrogen bonds between specific pairs of bases: adenine
bonded to thymine, guanine bonded to cytosine. The two strands of the double helix
coil in a manner that results in a major groove(1.2 nm wide) and a minor groove(600
pm wide). Crick’s “central dogma” asserted that the function of DNA was to store infor-
mation and pass it on to RNA, which would in turn use this information to direct the
synthesis of proteins. RNA, in the form of messenger RNA (mRNA), carries the infor-
mation from the DNA to ribosomes for the purpose of protein synthesis. The specific
ribonucleotide sequence in mRNA forms a message that determines the order in which
different amino acids are to be coupled during creation of the protein; each codon(or
“word”) along the mRNA chain consists of a three-ribonucleotide sequence that is spe-
cific for a given amino acid. From this dogma, three fundamental processes emerged:
- Replication: the process by which identical copies of DNA can be made so that
information is preserved and handed down from cell to cell - Transcription: the process by which the genetic information contained in DNA is
read and carried out of the nucleus on RNA - Translation: the process by which the genetic information being carried by RNA is
decoded and used to build proteins
These three fundamental processes are central targets in drug design.
ENDOGENOUS CELLULAR STRUCTURES 441