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| Questão | Responda |
| The majority of drug targets (receptors) are proteins coded for in the genome | DNA is transcribed into mRNA, which can then be translated at the ribosome to make a number of proteins: - enzymes - transporters - ion channels - receptors - pumps |
| How to clone a receptor gene | 1. Extract mRNA from the tissue desired to be cloned 2. Use biochemistry to convert mRNA to cDNA 3. Use PCR to amplify cDNA 4. Sepereate cDNA into seperate cells, culture them and screen with ligands in order to identify receptors. 5. sequence to reveal gene code. |
| Uses for gene code | - Identification of the gene sequence of a drug target - Allowing transfer of DNA from one organism to another - Modification of proteins - to derive the amino acid of a drug target - identification of chromosomes - Identification of links w/genetic diseases/variation between people |
| Amino acid sequence of drugs | - The amino acid sequence of drugs can be deciphered from the genome code. - It gives information on structure and function as well as identifying similar proteins and the domain of proteins. |
| How is the muscarinic Ach receptor different from the nicotinic Ach receptor? | - Ach works on 2 types of receptors: * nicotinic Ach receptors, which are ion channels * muscarinic Ach receptors, which are G-protein coupled receptors - Both of these types of receptors are made up of different specific proteins, which can be identified using genes |
| Components of a muscarinic Ach receptor (g-protein coupled receptor) | - Single protein - 7 trans-membrane domains - one Ach binding site - G-protein coupling region |
| Components of a nicotinic Ach receptor (ion channel) | - 5 protein subunits - 4 transmembrane domains - 2 Ach binding sites - Ion pore (cation selective) |
| Function: How muscarinic receptors work (G-proteins) | - binds Ach to deep pocket within the membrane - This binding transduces information in the receptor through structural change into a G-protein. - The G-protein is then activated, so it can go do its job ie activate an enzyme or switch on an ion channel. |
| Function: How nicotinic receptors work | - receptors are activated by Ach, when 2 molecules bind. - once one molecule binds, the infinity for the other goes up, so the second molecule binds more easily. - then an ion pore opens to allow Na+ to flow into the pore and out the other side. |
| Identification of protein families (similar proteins) | - Identifying genes allows us to sort receptors into families - this can be done in terms of function |
| Classification of receptors | *GPCRs- g-protein coupled receptors -class A; muscarinic receptor -class B; parathyroid hormone receptor -class C; GABAb receptor *Ion channel receptors - cys-loop eg nicotinic receptors - glutamate receptors - punnoreceptors *Intrinsic enzyme receptors - insulin receptors * DNA binding receptors - oestrogen |
| How knowing the structure of the ligand binding site may help rational drug design | - knowing the exact amino acids Ach binds to in the nicotinic Ach receptor allows pharmacologists to design agonists/antagonists accordingly. - Reverse pharmacology: - use a sequence common to a family of receptors eg actactggcgg - put this into a genome database - genome database will determine if it is belonging to a known receptor, a possible receptor or an unknown (orphan) receptor. |
| EG the family of G-protein coupled receptors | - 720 genes - 360 sensory receptors - 360 receptors |
| Pharmacogeonomics | - some diseases can be genetic - AND the reason why some drugs work well in some people but not in others can also be down to genetics. |
| Example of pharmacogeonomics: succinylcholine | - Sux is a depolarising neuromuscuar blocker with a breif duration and rapid onset. - Its uses are in tracheal intubation and ECT - in MOST people; sux is broken down by plasma cholinestherase enzymes, BUT.. about 1/3500 Caucasians have a variant gene that codes for plasma cholinestherase - this is a result of a point mutation, reducing the effictiveness of the enzyme to break down sux, meaning its effects last longer |
| Genetic adverse effects of drugs: example of halothene | - halothene- general anasthetic - in rare groups of patients it causes adverse reactions ie increased skeletal muscle emetabolism, muscle contractions, hypokalemia, malignant hypertension -Mechanism by which this occurs: *mutations in the SR calcium release channel mean that it is activated by halothene releasing calcium into the skeletal muscle, - this results in spontaneous contractions and previously listed side effects. |
| Solutions to adverse effects of halothene | - dantrodene blocks SR calcium release channel, and can therefore save the patient if given quickly enough |
| personalised medicine | - check genome first - perscribe suitable drug - reduces chances of adverse effects - increase clinical effectiveness - this has already started in oncology; breast cancer. often the proteins that the tumours express can define the treatment given. |
| Gene therapy | - simple concept; replace the disfunctioning gene. - but a number of technical difficulties; - you need to get the new gene into the correct cell. - stop the mutant gene from functioning - stop the new gene from disrupting other healthy genes - control the new gene expression * there has been some success in animal studies but cases of severe immune reactions in humans. |
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