Introduction to Medicinal Chemistry 3/e Chapter 1: Drugs and Drug Targets PDF

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 1 THE WHY & THE WHEREFORE: DRUGS AND DRUG TARGETS: an overview Contents 1. Cell Structure (8 slides) 2. Cell Membrane (5 slides) 3. Drug Targets (4 slides) 4. Intermolecular Bonding Forces (9 slides) 4.1...

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 1 THE WHY & THE WHEREFORE: DRUGS AND DRUG TARGETS: an overview Contents 1. Cell Structure (8 slides) 2. Cell Membrane (5 slides) 3. Drug Targets (4 slides) 4. Intermolecular Bonding Forces (9 slides) 4.1. Electrostatic or ionic bond 4.2. Hydrogen bonds (3 slides) 4.3. Van der Waals interactions 4.4. Dipole-dipole/Ion-dipole/Induced dipole interactions (4 slides) 5. Desolvation penalties 6. Hydrophobic interactions 7. Drug Targets - Cell Membrane Lipids (2 slides) 8. Drug Targets – Carbohydrates (2 slide) [32 slides] ©1  Drugs are compounds that interact with a biological system to produce a biological response. No drug is totally safe. Drugs vary in the side effects they might have. The dose level of a compound determines whether it will act as a medicine or as a poison.  Cells Basic building blocks of life Smallest living unit of an organism Grow, reproduce, use energy, adapt, respond to their environment A cell may be an entire organism as bacteria, protists, and yeast or it may be one of billions ofcells that make up the organism Cells May be Prokaryotic or Eukaryotic 4 1. Cell Structure ©1 ©1 2. Cell Membrane Proteins Exterior High [Na+] Phospholipid Bilayer Interior High [K+] ©1  Pol ar Head CH2CH2NMe3 Group O Polar Head O P O Group O CH2 CH CH2 O O Hydrophobi c Tails O O CH2CH2NMe3 Hydrophobic Tails O Polar Head O P O Group O CH2 CH CH2 O O O O Hydrophobic Tails ©1 ©1  Binding regions Drug Binding Drug Action/ Effect groups Intermolecular bonds Binding site Binding Drug site Drug Macromolecular target Macromolecular target Unbound drug Bound drug ©1 Induced fit is a model in biochemistry that describes how the binding of a ligand (such as a substrate, drug, or molecule) to a protein (like an enzyme or receptor) causes the protein to change its shape or conformation to better accommodate the ligand. ©1  Pharmacodynamics is the study of how drugs interact with their targets and produce a pharmacological effect. 4. Intermolecular bonding forces O Drug NH3 O Drug O H3N Target Target O ©1  - + - - + - Drug Y H X X H Y Target Target Drug ©1 HBD HBA HBA HBD  X H Y X H Y Hybridised 1s Hybridised orbital orbital orbital SP HBD HBA SP3 (Methane CH4) = 109o, SP2 (aluminium trihydride AlH3) = 120o, SP (Magnesium Hydride MgH2= 180o ) ©1  DRUG Hydrophobic regions + - Transient dipole on drug + - van der Waals interaction - + Binding site ©1  Van der Waals interactions are also referred to as London forces. Although the interactions are individually weak, there may be many such interactions between a drug and its target, and so the overall contribution of van der Waals interactions is often crucial to binding. ©1 − O Dipole moment + C R R Localised dipole moment R O C R Binding site Binding site ©1 R O − C + R R O − C + O H3N O C R Binding site Binding site ©1 ©1 H O H O H H H O O O C H C R R H R R O H O H O O H O H C R R Binding site Binding site Binding site Desolvation - Energy penalty Binding - Energy gain ©1  DRUG Drug Binding DRUG Hydrophobic Drug regions Water Binding site Binding site Structured water layer Unstructured water round hydrophobic regions Increase in entropy ©1  Hydrophobic interactions involve the displacement of ordered layers of water molecules which surround hydrophobic regions of molecules. The resulting increase in entropy contributes to the overall binding energy. Polar groups have to be desolvated before intermolecular interactions take place. This results in an energy penalty. Clinically useful drugs have a trade (or brand) name. Most structures produced during the development of a new drug are not considered for the clinic. They are identified by simple codes that are specific to each research group.  Hydrophilic OH Hydrophilic HO O Me OH O OH OH OH OH O OH HOOC Me H Me Me O O NH2 HO HO Amphotericin B ©1  OH OH CO2H HO2C Sugar Sugar OH HO OH HO OH HO OH HO OH HO OH HO OH HO CELL MEMBRANE OH HO OH HO OH HO OH HO OH HO OH HO OH HO Sugar HO2C OH Sugar OH CO2H ©1  Their presence on the cell surface, where they are often attached to proteins and lipids, forming glycoproteins and glycolipids. Carbohydrates play important roles in cell recognition, regulation and growth. Potential targets for the treatment of bacterial and viral infection, cancer and autoimmune disease Carbohydrate 'tag' Carbohydrates act as antigens Cell membrane Several drugs are carbohydrates or contain carbohydrates in their structure (streptomycin, zidovudine, acyclovir) ©1  Carbohydrates are more challenging to synthesis than peptides but offer a greater variety of potential novel structures The immune system relies on carbohydrates to distinguish between the body's own cells and foreign invaders (such as pathogens).  Complex carbohydrates coat the surfaces of cells and have the potential to carry the information necessary for cell-cell recognition. Glycolipids are lipids that form part of the membrane. They have a short carbohydrate chain covalently attached, and this is exposed on the outer surface of the cell. a glycolipid is usually composed of a hydrophobic tail made up of fatty acids. This allows the glycolipid to be embedded in the lipid bilayer of the cell membrane. The glycoplipids mainly have a communicative role, often acting as markers for cellular recognition. Additionally, they provide stability for the cell and help cells join to other cells to form tissues.  Glycoproteins are integral membrane proteins. Like glycolipids, they have short carbohydrate chains covalently attached to polypeptide chain and these hydrocarbons chain are exposed on the outer surface of the cell. Has a hydrophobic region (non-polar) that interacts with the hydrophobic interior of the membrane's phospholipid bilayer. This portion helps anchor the glycoprotein within the membrane. Glycoprotein play crucial part in cell-cell recognition, protection and immune response