Medicinal Chemistry Revision PDF

Revision Document for AP0415 Medicinal Chemistry Chapter 1: Introduction to Medicinal Chemistry and Drug Discovery 1.1 What is a Drug? Definition: Drugs are compounds that interact with a biological system to produce a biological response. Classification: o Natu...

Revision Document for AP0415 Medicinal Chemistry Chapter 1: Introduction to Medicinal Chemistry and Drug Discovery 1.1 What is a Drug? Definition: Drugs are compounds that interact with a biological system to produce a biological response. Classification: o Natural products: Derived from plants, animals, or minerals (e.g., quinine from Cinchona bark). o Fermentation products: Produced by microorganisms (e.g., penicillin from Penicillium notatum). o Semi-synthetics: Modified natural products (e.g., semi-synthetic penicillins). o Completely synthetic: Man-made compounds (e.g., aspirin). Selective Toxicity: Drugs should be toxic to problem cells (e.g., cancer cells) but not normal cells. 1.2 Drug Discovery Process Stages: 1. Target Identification: Identify a biological target (e.g., protein, enzyme, receptor) involved in a disease. 2. Hit Generation: Identify initial compounds (hits) that interact with the target. 3. Lead Optimization: Improve the properties of lead compounds (e.g., efficacy, safety, pharmacokinetics). 4. Preclinical Development: Test drug candidates in non-human systems for safety and efficacy. 5. Clinical Trials: ▪ Phase I: Safety and dosage in healthy volunteers. ▪ Phase II: Efficacy and side effects in patients. ▪ Phase III: Confirm efficacy and monitor side effects in a larger patient population.  6. Regulatory Approval: Submit a New Drug Application (NDA) to regulatory agencies. 7. Post-Marketing Surveillance: Monitor the drug’s safety and effectiveness after approval. 1.3 Drug Metabolism Purpose: Convert drugs into more polar molecules for easier excretion. Phases: o Phase I: Functionalization reactions (e.g., oxidation, reduction, hydrolysis). o Phase II: Conjugation reactions (e.g., glucuronidation, sulfation, glutathione conjugation). Chapter 2: Drug Targets and Mechanisms of Action 2.1 Drug Targets Types of Drug Targets: o Enzymes: Catalyze biochemical reactions (e.g., ACE inhibitors). o Receptors: Bind ligands to trigger cellular responses (e.g., GPCRs). o Ion Channels: Allow ion flow across membranes (e.g., ligand-gated ion channels). o Nucleic Acids: DNA/RNA (e.g., anticancer drugs). o Transporters: Move molecules across membranes (e.g., neurotransmitter reuptake inhibitors). 2.2 Enzyme Inhibition Types of Inhibitors: o Reversible: ▪ Competitive: Competes with the substrate for the active site. ▪ Non-competitive: Binds to a site other than the active site, altering enzyme shape. ▪ Uncompetitive: Binds only to the enzyme-substrate complex. o Irreversible: Binds covalently to the enzyme, permanently inactivating it.  Examples: o Aspirin: Inhibits cyclooxygenase (COX), reducing prostaglandin synthesis. o Sulphonamides: Inhibit dihydropteroate synthase, blocking folate synthesis in bacteria. 2.3 Receptors and Ligands Agonists: Activate receptors, producing a biological response (e.g., morphine activates opioid receptors). Antagonists: Bind to receptors but do not activate them, blocking the action of agonists (e.g., beta-blockers). Chapter 3: Drug Metabolism 3.1 Phase I Metabolism Reactions: o Oxidation: Adds oxygen or removes hydrogen (e.g., cytochrome P450 enzymes). o Reduction: Adds hydrogen or removes oxygen. o Hydrolysis: Breaks bonds using water (e.g., ester or amide hydrolysis). Examples: o Aromatic Hydroxylation: Adds a hydroxyl group to an aromatic ring. o Aliphatic Hydroxylation: Adds a hydroxyl group to an aliphatic chain. o Dealkylation: Removes an alkyl group (e.g., N-dealkylation, O- dealkylation). 3.2 Phase II Metabolism Conjugation Reactions: o Glucuronidation: Adds glucuronic acid to increase water solubility (e.g., morphine glucuronide). o Sulfation: Adds a sulphate group (e.g., minoxidil sulphate). o Glutathione Conjugation: Detoxifies reactive metabolites (e.g., NAPQI from paracetamol).  o Amino Acid Conjugation: Adds glycine or glutamine (e.g., salicyluric acid from aspirin). o Acetylation: Adds an acetyl group (e.g., procainamide acetylation). o Methylation: Adds a methyl group (e.g., catechol-O-methylation). Chapter 4: Enzymes as Drug Targets 4.1 Angiotensin-Converting Enzyme (ACE) Inhibitors Mechanism: Inhibit ACE, preventing the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. Examples: o Captopril: Contains a thiol group that binds to the zinc ion in ACE. o Enalaprilat: Replaces the thiol group with a carboxylate group, reducing side effects. o Lisinopril: Contains a lysine side chain that binds to additional residues in ACE. 4.2 Acetylcholinesterase (AChE) Inhibitors Mechanism: Inhibit AChE, leading to acetylcholine buildup and overstimulation of the nervous system. Examples: o Nerve Gases (e.g., Sarin): Irreversibly inhibit AChE, causing severe neurological effects. o Organophosphate Insecticides (e.g., Parathion): Inhibit AChE in insects, leading to paralysis and death. Chapter 5: Antibiotics and Drug Resistance 5.1 Antibiotics Mechanisms of Action: o Inhibition of Cell Wall Synthesis: Penicillins, cephalosporins. o Inhibition of Protein Synthesis: Tetracyclines, chloramphenicol. o Inhibition of Nucleic Acid Synthesis: Quinolones, rifamycins.  o Disruption of Cell Membrane: Polymyxins. o Inhibition of Metabolic Pathways: Sulphonamides. 5.2 Drug Resistance Causes: o Genetic Mutations: Bacteria develop resistance through mutations. o Horizontal Gene Transfer: Bacteria share resistance genes. o Overuse/Misuse of Antibiotics: Accelerates resistance development. Prevention: o Antimicrobial Stewardship: Responsible use of antibiotics. o Infection Control: Hand hygiene, sanitation, isolation. o Research and Development: New antibiotics, vaccines, and diagnostics. Chapter 6: Pharmacokinetics and Pharmacodynamics 6.1 Pharmacokinetics (ADME) Absorption: Movement of a drug from the administration site to the bloodstream. Distribution: Movement of a drug throughout the body. Metabolism: Chemical alteration of a drug (e.g., Phase I and Phase II reactions). Excretion: Removal of the drug and its metabolites from the body (e.g., via urine or bile). 6.2 Pharmacodynamics Dose-Response Relationship: o ED50: Dose that produces 50% of the maximum effect. o LD50: Dose that is lethal to 50% of the population. o Therapeutic Index: Ratio of LD50 to ED50 (higher values indicate safer drugs). Receptor Binding: o Agonists: Activate receptors. o Antagonists: Block receptors. Chapter 7: Case Studies in Medicinal Chemistry 7.1 Aspirin Mechanism: Inhibits cyclooxygenase (COX), reducing prostaglandin synthesis and inflammation. Metabolism: o Hydrolysis to salicylic acid. o Glucuronidation or glycine conjugation to form salicyluric acid. 7.2 Paracetamol Mechanism: Inhibits prostaglandin synthesis in the CNS, reducing pain and fever. Metabolism: o Glucuronidation (primary metabolite in adults). o Sulfation (primary metabolite in children). o Oxidation to NAPQI (toxic metabolite, detoxified by glutathione). 7.3 Sulphonamides Mechanism: Inhibit dihydropteroate synthase, blocking folate synthesis in bacteria. Selective Toxicity: Bacteria synthesize folate, while humans obtain it from their diet. Chapter 8: Advanced Topics in Medicinal Chemistry 8.1 Bioinformatics and Drug Design Role of Bioinformatics: Combines biology, computer science, and information technology to analyze biological data. Applications: o Target Identification: Identify potential drug targets using genomic and proteomic data. o Virtual Screening: Predict how well compounds bind to targets using computational models.  o QSAR (Quantitative Structure-Activity Relationship): Correlate molecular properties with biological activity. 8.2 Personalized Medicine Role of Pharmacogenomics: Study how genetic variations affect drug response. Applications: o Tailor drug treatments to individual patients based on their genetic makeup. o Reduce adverse effects and improve efficacy. Chapter 9: Summary and Key Takeaways 9.1 Key Concepts Drug Discovery: A multi-step process involving target identification, lead optimization, and clinical trials. Drug Metabolism: Converts drugs into more polar molecules for excretion, involving Phase I and Phase II reactions. Enzyme Inhibition: A common mechanism of action for many drugs, including antibiotics and ACE inhibitors. Receptors and Ligands: Agonists activate receptors, while antagonists block them. Pharmacokinetics and Pharmacodynamics: Describe how drugs move through the body (ADME) and how they produce their effects (dose-response relationships). 9.2 Future Directions Combatting Drug Resistance: Develop new antibiotics and promote responsible use of existing ones. Advances in Drug Design: Use computational tools and bioinformatics to accelerate drug discovery. Personalized Medicine: Tailor treatments to individual patients based on genetic and molecular data. Molecules 1. Fundamental Biomolecules A. Carbohydrates Monosaccharides: o Basic units (e.g., glucose, fructose) o D/L configuration based on chiral carbon o Cyclic forms (α/β anomers) Polysaccharides: o Starch (α-1,4 with α-1,6 branches) - energy storage o Cellulose (β-1,4) - structural o Glycogen - animal starch, highly branched B. Nucleic Acids DNA Structure: o Double helix with antiparallel strands o Base pairing: A-T (2 H-bonds), G-C (3 H-bonds) o Phosphodiester backbone (5'→3') RNA Types: o mRNA: carries genetic code o tRNA: brings amino acids (anticodon matches codon) o rRNA: ribosome structure 2. From DNA to Protein A. Central Dogma Flow 1. Replication (DNA → DNA) o High fidelity (error rate 10⁻⁸-10⁻¹⁰) 2. Transcription (DNA → mRNA) o RNA polymerase o Post-transcriptional modifications  3. Translation (mRNA → Protein) o Ribosomes read codons o tRNA delivers amino acids o Peptide bond formation B. Key Processes tRNA Charging: o Aminoacyl-tRNA synthetases attach correct amino acid o Requires ATP Protein Synthesis: o Initiation: Start codon (AUG), Shine-Dalgarno sequence o Elongation: Peptide bonds form (GTP hydrolysis) o Termination: Stop codons (UAA, UAG, UGA) 3. Protein Structure & Function A. Structural Levels 1. Primary: Amino acid sequence 2. Secondary: o α-helices (H-bonds parallel to axis) o β-sheets (parallel/antiparallel) o Turns and loops 3. Tertiary: 3D folding o Stabilized by hydrophobic effect, H-bonds, disulfide bridges 4. Quaternary: Multiple subunits (e.g., hemoglobin) B. Protein Folding Driving Forces: o Hydrophobic collapse (nonpolar residues inside) o Hydrogen bonding o Chaperones assist folding Misfolding Diseases:  o Prion diseases (α-helix → β-sheet) o Cystic fibrosis (CFTR mutation) 4. Drug Design Principles A. Structure-Activity Relationships (SAR) Key Concepts: o Bioisosteres: Replace groups while maintaining activity o Lipinski's Rule of 5 (oral drug guidelines) o Partition coefficient (log P) measures hydrophobicity B. QSAR (Quantitative SAR) Parameters: o Hydrophobicity (π constant) o Electronic effects (Hammett σ constant) o Steric factors (Taft Es) Applications: o Optimize drug absorption (e.g., balance hydrophilic/hydrophobic) o Reduce toxicity (e.g., replace toxicophores) 5. Membranes & Drug Transport A. Membrane Structure Phospholipid bilayer (amphipathic) Proteins: integral (transmembrane) vs. peripheral Composition varies (e.g., myelin = 79% lipid, erythrocyte = 44% lipid) B. Drug Absorption Lipinski's Rules: o MW < 500 o ≤5 H-bond donors o ≤10 H-bond acceptors o log P < 5 Polar Drugs:  o Pinocytosis (cell "drinking") for large polar molecules o Transport proteins for small polar molecules Summary Sheet Carbohydrates Energy (starch), structure (cellulose) Glycosidic bonds: α (starch) vs β (cellulose) Nucleic Acids DNA: A-T, G-C, double helix RNA: single-stranded, U instead of T Protein Synthesis DNA → mRNA → protein tRNA matches codons, ribosomes make peptide bonds Protein Structure Levels: 1°→4° Folding driven by hydrophobic effect Drug Design Optimize log P, use bioisosteres Follow Lipinski's rules for oral drugs Membranes Lipid bilayer with proteins Drugs need right balance of polar/nonpolar