1922 L1

1. Covalent bond 

   • Strongest and often result in irreversible drugs binding to receptor  

   • Receptor degraded and new synthesis of target protein required so have a prolonged effect  

2. Ionic bonds 

   • Moderate strength bonds formed by electrostatic attraction  

   • Ability to form ionic bonds increase as drug diffuses closer to target  

3. Hydrogen bonds 

   • Weak so alone will not support drugs target interaction —> multiple hydrogen bond required to stabilise drugs target complex  

4. Hydrophobic interactions 

   • Occur between non-polar molecules  

   • Very weak and require that molecule and receptor are in very close proximity  

Lead compound --> chemical compound that shows promising biological or pharmacological activity and used as a starting point for developing a new drug  

• Porins transport polar molecules across the outer membrane of gram negative bacteria  

• NPC1L1 protein transports cholesterol across lipid membrane of gastrointestinal tract epithelial cells—> inhibit by ezetimibe results in decrease absorption of cholesterol from the small intestine —> increase in low density lipoprotein uptake and its removal from the plasma  

Methotrexate is an anti-cancer agent which inhibits the dihydrofolate reductase enzyme —> produce by Bioisosteric replacements in natural substrate of enzyme  

• Sulfanilamide has similar molecular dimensions and properties to PAABA so is mistaken for it by dihydropteroate synthetase  

• Sulfonamides bind to PABA binding domain of the active site of dihydropteroate synthetase and some are incorporated into macromolecule 

• Once sulfonamide is incorporated into macromolecule further reaction with L-glutamic acid will not produce folic acid  

• Reversive by addition of excess PABA result in the formation of folic acid 

• Nucleic acids are target for chemotherapeutic agents  

• Drugs can be 

  • chain terminators (terminates further elongation of chain) 

  • covalent binders (form a covalent bond to electron rich sites on the DNA) 

  • intercalators (planar molecules which can slide between the base pairs) 

Enzyme catalyse steps in the biosynthesis of many cellular products --> drugs can act as inhibiting and enzyme or by acting as a false substrate  

• Proteins and nucleic acids form critical links in all biochemical processes 

• Modulating a malfunctioning biochemical process may alleviate disease symptoms  

Magic bullet --> drugs or treatment that selectively targets and eliminates disease causing agents or cells  while leaving healthy cells unharmed  

• Can be agonist --> bind to receptor -->biological response --> high efficacy fully agonist / intermediate efficacy partial agonist  

• Can be antagonist --> bind to receptor --> no biological response (antagonist prevents agonist from binding)  

•  Three main types —> mu, kappa and delta 

• All G protein coupled receptor 

• Binding of agonist induce conformational change —> this activates the Gi protein and leads to a series of event which result in analgesia  

• Paracetamol < codeine < morphine (increase in treating pain intensity)  

• Affinity of codeine for O-R is less than morphine —> has to be metabolized to morphine4 to exert its optimal analgesic activity  

• A pharmacophore is the group of structural features required for the optimal interaction of a drug with it target 

Ca channel blockers act on voltage gated Ca channels in cardiac muscle and blood vessels —> decrease Ca to reduction in muscle contraction —> decrease force of contraction of the heart and lead to vasodilation so lower blood pressure  

• Drug in an inactive form. Once administered it is metabolised to give active form of drugs.  

• Use for 

  • Alter solubility 

  • Improve membrane permeability  

  • Slow release of active agent 

  • Mask drug toxicity or side effects  

Bioisosteric groups are substituents or functional groups with related physical and/ or chemical properties  

• Use to decrease toxicity, modify activity or change pharmacokinetics 

• Aim to enhance biological/ physical properties by making small changes in a structure  

• Isometric replacements may modulate size, conformation, H-bonding, pKa, solubility, stability