Secti。nB-D Drug'smuggling' Carrier proteins provide a method by which polar drugs can be transported across fatty cell membranes. The drug is attached to a natural guest such as a nucleic acid base. The latter is recognized by its carrier protein, which then muggles the compound into the cell. Uracil mustard (Fig 3)is an anti-cancer drug that is smuggled into cells in this way. The uracil portion of the drug is recognized by the transport protein, while the mustard portion is an alkylating agent which reacts with DNA and prevents DNA from functioning. Some drugs are sufficiently similar in structure to the natural guest that they are accepted by carrier proteins. For example, L-dopa(Fig. 3)is used for the treatment of Parkinsons disease. Because it is an amino acid, it is smuggled across the blood-brain barrier by amino acid transport protein Mustard 3. Uraci mustard and L-doba
Sectlon B-Drug targets B030909096106B复旦图书馆 B4 STRUCTURAL PROTEINS Key Notes Structural proteins are not usually drug targets. An exception is tubulin, which polymerizes to form microtubules that serve a variety of cellula Drugs that inhibit the polymerization or depolymerization of microtubules are potentially useful in the treatment of arthritis and various tumors Related topl Quantitative structure-activity relationships(G5) Structural proteins include cellulose in plants and collagen in animals. In general, structural proteins are not important drug targets. An exception is a protein called tubulin, which can polymerize into small tubes called micro- tubules (Fig. 1). These microtubules have various cellular functions and are important to the structural integrity and mobility of cells Polymerization Depolymerization Tubulin Fig. 1. Tubulin and microtubules. Reproduced from An Introduction to Medicinal Chemistry, L Patrick, 2001, by permission of Oxford University Press. Microtubules are also important to the process of cell division (Fig. 2).When a cell is about to divide, the microtubules are depolymerized to their tubulin monomer units. These are then repolymerized in order to form a spindle struc- ture, which pushes the two daughter cells apart and is the framework by which the chromosomes are transferred to each of the daughter cells duced from An Introduction to Medicinal Chemistry, G L Patrick, 2001, by permission of Oxford University Press
Drugs acting on Drugs that depolymerize microtubules could be useful in the treatment of arthritis by reducing the mobility of inflammatory cells called neutrophils, thus hindering them from entering joint Drugs that inhibit the depolymerization or repolymerization of microtubules inhibit cell division and are potentially useful in the treatment of cancer. Vincristine is an anticancer drug that inhibits polymerization, whereas taxol is a drug that inhibits depolymerization(Fig 3) H,C COME OH O Fig 3. Drugs acting on microtubules
Section B- Drug targets B5 NUCLEIC ACIDS Key Notes Nucleic acids There are two types of nucleic acid-DNA and RNA DNA acts as the genetic blueprint for the cell. There are three types of RNA-messenger (mRNA), ribosomal (rRNA) and transport(tRNA) EDNA inter DNa intercalators contain a planar aromatic or heteroaromatic system that can slip between two sets of base pairs in DNA. van der Waals interactions help to hold the ring system in place. The ring system other y has polar substituents that can interact with phosphate groups Alkylating agents Alkylating agents contain two electrophilic groups which react with nucleophilic groups in DNA. Covalent bonds are formed that tether the drug to the same strand of dNa or crosslink the strand Chain cutters are drugs that promote the cutting of the dNa strand and inhibit the cells repair processes. L Antisense therapy Antisense therapy involves the design of a molecule that contains complementary base pairs to a segment of mRNA Base pairing binds the drug to the mRNA and prevents the mRNA's message being read piton of rRNA Several important antibiotics bind to rRNA and prevent protei Related topIcs Binding interactions(G2) ional groups as binding oups(G3) Nucleic acids Nucleic acids are targets for several important drugs, including various anti- microbial and anticancer agents. There are two types of nucleic acid-deoxy ribonucleic acid (DNA)and ribonucleic acid(RNA). DNA is the genetic blueprint for the cell and contains all the information required for the biosyn thesis of the cells proteins. It consists of two polymeric oligonucleotide strands, which form a double helix (Fig. 1). Each strand of the helix is made up of a deoxyribose sugar-phosphate backbone, with a nucleic acid base linked to eack sugar moiety. The double helix is held together by hydrogen bonds, which link the nucleic acid bases of one strand to the bases of the other strand. The nucleic acid pairings are such that adenine is paired with thymine, while guanine is linked with cytosine. This means that one DNA strand is complementary to the other and explains how genetic information can be passed on from cell to cell, and from generation to generation. Unraveling of the dNA helix means that each strand can act as a template for the synthesis of two identical DNA mole- ules, which will be transferred to daughter cells. The nucleic acid bases and the order in which they occur in the DNA molecule determine the genetic code
Section B-Drug targets Thymine Adenine BASE PAIRING RNA molecules have a similar primary structure to DNA. However, the sugar is ribose rather than deoxyribose, and the nucleic acid base uracil is present rather than thymine (Fig. 2). There are also other less common nucleic acid bases present in smaller quantities OHOH Ribose Deoxyribose Fig. 2. Ribose, deoxyribose and uracH. RNA is a single polymer and does not form a double helix. There are three es of RNA- messenger RNA (mRNA), ribosomal RNA (RNA) and transfer RNA (tRNA), all of which are required for the biosynthesis of proteins Messenger RNA acts as a 'photocopy of specific regions of the DNA and carries the genetic code for a specific protein. Ribosomal RNA is present in Aming the'adapter,, which is used to interpret the genetic code and has two binding egions (Fig 3). One binding region consists of three nucleic acid bases, which are complementary to a specific triplet of nucleic acid bases on mRNA, while the other binding region recognizes a specific amino acid. In this way, a specific triplet of nucleic acid bases corresponds to a particular amino acid. There are different tRNa molecules for each of the natural amino acids, each recognizing a different nucleic acid base triplet Binding regio During protein biosynthesis, rRNA attaches to one end of an mRNa molecule and then travels along the strand(Fig. 4). As it travels along the ig.3 Transport RNA strand, the nucleic acid bases on the mRNa are read as triplets. The tRNA that (tANA recognizes that triplet is bound and brings the amino acid coded by that triplet