BIOLCHEM 415 1st Edition Lecture 8Outline of Last Lecture I. Enzyme kineticsII. Reversible and Irreversible inhibition of enzymesIII. Allosteric regulation – binding of a molecule at a site other than the active siteOutline of Current Lecture IV. Basics of Drug actionV. Examples of three different classes of drugs: β-lactam antibiotics, HIV anti-retrovirals, andnon-steroidal anti-inflammatory drugs (NSAIDS)Current LectureProperties of effective drugs- must be easily administered- minimal toxicity and side effects- survive in body long enough to reach target area and to have an effect- must not modulate properties of anything other than targets- be cleared from the body in a reasonable period of time- diminishes toxicityTwo Approaches to drug deliveryA) Compound  Physiological effect  Molecular target- includes natural products- aspirin, penicillin, quinineB) Molecular target  Compound  Physiological effect- includes rationally designed drugs- HIV retro-viralsThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.Drugs as Ligands to Enzymes or Receptors- ligand binding to receptor or enzyme- alters receptors/enzymes chemical conformationDrugs as Competitive Inhibitors- Drugs will bind with the enzymes active site and block substrate bindingAbsorption, Distribution, Metabolism, and Excretion of Drugs- drugs will be absorbs into the bloodstream for transport- it will bind with the target compartments- will cycle through the body and then be excreted with any bound moleculesHalf-life of a drug- will determine administration- determined by rate that is eliminated by oxidation, conjugation to another molecule, and/or excretionAlbumin Carries Lipophlic Drugs in the Blood - lipophilic – tending to dissolve in or combine with lipids or fats- serum albumin binds to many drugs- transports them throughout the body via cardiovascular systemMetabolism of Drugs Alters their Activity- ex: oxidation of Ibuprofen (NSAID) by Cytochrome P450- increases its solubility - aids in drug’s excretion from bodyHigh Drug Levels can = Cytotoxicity- ex: Hepatotoxicity of Anetaminophen (Tylenol)- depletes glutathione (GSH)- irreversible liver damageβ-lactam Antibiotics- all have a β-lactam ring structure- R group distinguishes the different antibiotics- Penicillin- founding member- discovered by Alexander Flemming, 1928- secreted by mold Penicilliumnotatum- kills bacteria- inhibits cell wall biosynthesis in bacteria- peptidoglycan (bacterial cell wall)- peptides covalently linked to polysaccharide- penicillin forms a new peptide bond in the cell wall- glycopeptidetranspeptidase- glycopeptidetranspeptidase mechanisms- cleaves the peptide bond at the C-terminus of the tetrapeptide precursor - forms acyl-enzyme intermediate- transfers acyl-enzyme intermediate to N-terminus of pentaglycine bridge- new peptide bond- suicide inhibitor of glycopeptidetranspeptidase- inactivatesenxyme by forming penicilloyl-enzyme complex- other examples - carbenicillin- amoxicillin- cloxacillin- β-lactamase hydrolyzes the β-lactam ring of compounds with small R groups (e.g. pencillin)- Clavulanic Acid can be used to overcome this- suicide inhibitor- similar structure to β-lactam ringHIV Antiretroviral Drugs- HIV is a retrovirus- primary cause of AIDS- retroviral drugs have 3 primary targets- HIV Reverse Transcriptase- transcribes virus’s RNA genome into DNA- HIV Integrase- incorporates virus’s DNA into host’s genomic DNA- HIV Protease- cleaves the polyprotein (encoded in viral DNA) into viral proteins- rational design of drugs that inhibit HIV Protease- aspartyl protease- inhibitors that look like peptides- ex: Indinavir- Impact of antiretroviral drugs in HIV treatment- HIV rapidly mutates which leads to resistance to individual antiretroviral drugs- combination therapy- treating with multiple drugs can prevent HIV replication and mutationNon-steroidal Anti-Inflammatory Drugs (NSAIDS)- NSAIDS inhibit cyclooxygenase (COX)- COX catalyzes first step in prostaglandin synthesis- convertsarachidonic acid to prostaglandin H2 in two steps- prostaglandinscause contraction or dilation of blood vessels- regulates inflammation and induces fevers- common NSAIDS target- examples- Acetylsalicylic Acid (aspirin)- ibuprofen- naproxen (aleve)- mechanism of COX inhibition by aspirin- aspirin transfers its acetyl group to the hydroxyl group of Ser530 in COX- obstructs hydrophobic channel leading to active site- irreversibly inhibits COX- structure of ibuprofen bound to COX- binds reversibly in hydrophobic channel leading to COX active site- blocksarachidonate binding- Naproxen competitively inhibits COX by binding in this