Pharmaceutical Chemistry: Drug Discovery

• Pharmaceutical chemistry involves studying drugs, their development, synthesis, and mechanisms within the body
• Combines chemistry, pharmacology, and other biological expertise
• Aims to design and develop new drugs
• Ensures medicines are of high quality and used appropriately

Drug Discovery and Development

• Discovering new chemical entities for disease treatment is a part of drug discovery
• Identifying a disease target, finding a lead compound, and optimizing its structure are steps in this process
• Target identification pinpoints specific molecules involved in disease, such as proteins, enzymes, or receptors
• Lead discovery identifies compounds that interact with the target
• High-throughput screening tests large compound libraries
• Lead optimization enhances the lead compound’s potency, selectivity, and pharmacokinetic properties through structural modification
• Preclinical studies evaluate drug safety and efficacy in vitro (cell cultures) and in vivo (animals)
• Clinical trials in humans assess drug safety and efficacy
• Phase I trials focus on safety
• Phase II trials focus on efficacy and side effects
• Phase III trials confirm efficacy and monitor adverse reactions
• Regulatory approval, such as from the FDA in the United States, is needed before marketing a drug

Chemical Synthesis of Drugs

• Chemical synthesis creates drug molecules through chemical reactions
• It starts with simple materials and builds up the complex drug structure
• Synthetic routes are designed to be efficient, cost-effective, and scalable
• Protecting groups safeguard specific functional groups during chemical reactions
• Reactions need to be highly specific for desired product
• Purification and characterization, including chromatography, NMR, and MS, ensure drug purity and identity
• Stereochemistry is important, as different stereoisomers can have different biological activities

Drug-Receptor Interactions

• Drugs interact with targets like receptors, enzymes, and ion channels to produce therapeutic effects
• Receptors are proteins that bind molecules like hormones or neurotransmitters, initiating a cellular response
• Chemical bonds, including ionic, hydrogen, and van der Waals forces, govern these interactions
• Agonists activate receptors, producing a biological response
• Antagonists block receptors, preventing activation
• Selectivity is the ability of a drug to bind a specific target
• Highly selective drugs are less likely to cause side effects
• Structure-activity relationship (SAR) studies determine how drug structure affects activity

Pharmacokinetics

• Pharmacokinetics describes how the body affects a drug (ADME: absorption, distribution, metabolism, excretion)
• Absorption is how a drug enters the bloodstream
• Factors include administration route, drug properties, gut pH, and motility
• Distribution is how a drug travels to tissues and organs
• Factors include blood flow, tissue permeability, and plasma protein binding
• Metabolism is the chemical modification of a drug, often in the liver, by enzymes like cytochrome P450s
• Metabolism can activate or inactivate a drug
• Excretion is how the body eliminates a drug via the kidneys (urine) and liver (bile)
• Bioavailability is the fraction of a drug dose that reaches systemic circulation
• Half-life is the time for drug concentration to decrease by half

Pharmacodynamics

• Pharmacodynamics describes how a drug affects the body, including mechanisms of action and therapeutic effects
• Dose-response relationships link drug dose and effect magnitude
• Therapeutic index measures drug safety as the ratio of toxic dose to therapeutic dose
• Side effects are unwanted effects of a drug
• Drug interactions can alter pharmacokinetic or pharmacodynamic effects of drugs taken together

Prodrugs

• Prodrugs are inactive compounds converted to active drugs in the body via enzymatic or chemical reactions
• Prodrugs improve drug absorption, distribution, or other pharmacokinetic properties
• A prodrug may be more soluble or cross cell membranes more easily than the active drug

Drug Metabolism

• Biotransformation, or drug metabolism, involves enzymatic modification of drugs
• Phase I reactions involve oxidation, reduction, or hydrolysis, introducing or exposing a functional group
• Cytochrome P450 enzymes are key in Phase I metabolism
• Phase II reactions involve conjugation, attaching a molecule to enhance water solubility and facilitate excretion
• Glucuronidation, sulfation, and acetylation are common Phase II reactions
• Genetic variations in drug-metabolizing enzymes can cause varied drug responses

Quantitative Structure-Activity Relationships (QSAR)

• QSAR correlates drug molecule structure with biological activity
• It develops mathematical models linking physicochemical properties (lipophilicity, electronic properties, steric effects) to potency
• QSAR models predict new compound activity and guide the design of more potent drugs

Modern Techniques

• High-Throughput Screening (HTS) screens large compound libraries for activity against targets
• Combinatorial chemistry quickly generates many compounds
• Structure-based drug design uses 3D structure of target proteins to design high-affinity drugs
• Computer-aided drug design (CADD) uses computational methods to discover, design, and optimize drug candidates
• Molecular modeling and simulation study drug-receptor interactions and predict drug behavior
• Omics technologies (genomics, proteomics, metabolomics) identify new drug targets and elucidate drug action and toxicity mechanisms