💊Medicinal Chemistry Unit 6 – Drug Targets and Action Mechanisms

Key Concepts

• Drug targets are biological molecules (proteins, nucleic acids, lipids, carbohydrates) that drugs interact with to produce therapeutic effects
• Drug-target interactions involve specific binding between a drug molecule and its target, which can be reversible or irreversible
• Pharmacodynamics describes the relationship between drug concentration at the target site and the resulting pharmacological effect
  • Includes concepts such as dose-response curves, efficacy, potency, and therapeutic index
• Mechanisms of action refer to the specific biochemical processes by which a drug produces its pharmacological effects
  • Can involve modulation of enzyme activity, receptor signaling, ion channels, or gene expression
• Drug resistance occurs when a drug loses its effectiveness against a particular disease or condition over time
  • Can be caused by mutations in the drug target, alterations in drug metabolism, or activation of compensatory pathways
• Drug selectivity refers to the ability of a drug to specifically interact with its intended target while minimizing off-target interactions
  • High selectivity reduces the risk of adverse effects and improves therapeutic outcomes

Types of Drug Targets

• Enzymes catalyze biochemical reactions and can be targeted by drugs to inhibit or enhance their activity (kinases, proteases)
• Receptors are proteins that bind to specific ligands (neurotransmitters, hormones) and mediate cellular responses
  • G protein-coupled receptors (GPCRs) are the largest family of drug targets and are involved in various physiological processes (beta-adrenergic receptors, opioid receptors)
  • Ligand-gated ion channels are receptors that open or close in response to ligand binding, allowing the flow of ions across the cell membrane (nicotinic acetylcholine receptors, GABA receptors)
• Transporters are proteins that facilitate the movement of molecules across biological membranes (serotonin transporter, glucose transporter)
• Nucleic acids (DNA, RNA) can be targeted by drugs to modulate gene expression or inhibit viral replication (antisense oligonucleotides, small interfering RNAs)
• Structural proteins (tubulin, actin) can be targeted by drugs to disrupt cellular processes such as cell division and migration (microtubule-targeting agents)

Drug-Target Interactions

• Binding affinity refers to the strength of the interaction between a drug and its target, often expressed as the dissociation constant (Kd)
  • High-affinity interactions are characterized by low Kd values and are more likely to produce potent pharmacological effects
• Binding specificity describes the ability of a drug to selectively interact with its intended target over other molecules
  • Determined by the complementarity of the drug's chemical structure to the target's binding site
• Covalent interactions involve the formation of chemical bonds between the drug and its target, leading to irreversible binding (aspirin, penicillin)
• Non-covalent interactions include hydrogen bonding, van der Waals forces, and electrostatic interactions, which allow for reversible binding
• Allosteric modulation occurs when a drug binds to a site distinct from the target's active site, causing conformational changes that affect the target's function (benzodiazepines, positive allosteric modulators of GABA receptors)

Pharmacodynamics

• Dose-response curves depict the relationship between drug concentration and pharmacological effect, typically following a sigmoidal shape
  • Efficacy refers to the maximum effect a drug can produce, while potency is the drug concentration required to produce 50% of the maximum effect (EC50)
• Agonists are drugs that activate their targets, producing a pharmacological response (morphine, an agonist of opioid receptors)
  • Full agonists elicit the maximum response, while partial agonists produce submaximal effects even at high concentrations
• Antagonists are drugs that inhibit the activity of their targets, blocking the effects of endogenous ligands or agonists (naloxone, an antagonist of opioid receptors)
  • Competitive antagonists compete with agonists for binding to the target, while non-competitive antagonists bind to allosteric sites or irreversibly inactivate the target
• Therapeutic index is the ratio of a drug's toxic dose to its effective dose, indicating the drug's safety margin
  • A high therapeutic index suggests a wide safety margin, while a low therapeutic index indicates a narrow range between therapeutic and toxic doses

Mechanisms of Action

• Enzyme inhibition can be achieved through competitive, non-competitive, or irreversible mechanisms
  • Competitive inhibitors compete with the substrate for binding to the enzyme's active site (methotrexate, dihydrofolate reductase inhibitor)
  • Non-competitive inhibitors bind to allosteric sites, reducing the enzyme's activity without affecting substrate binding (capsazepine, a non-competitive inhibitor of TRPV1)
• Receptor agonism involves the activation of receptors by drugs, leading to downstream signaling cascades and cellular responses
  • Agonists can be selective for specific receptor subtypes, allowing for targeted therapeutic effects (salmeterol, a selective beta-2 adrenergic receptor agonist)
• Receptor antagonism involves the inhibition of receptor function by drugs, preventing the binding or action of endogenous ligands
  • Antagonists can be used to treat conditions characterized by excessive receptor activation (propranolol, a beta-adrenergic receptor antagonist used to treat hypertension and anxiety)
• Ion channel modulation can involve the opening or closing of ion channels, altering the flow of ions across cell membranes
  • Drugs can act as channel activators (diazepam, a GABA receptor activator) or blockers (lidocaine, a sodium channel blocker)
• Gene expression modulation can be achieved through the use of drugs that target transcription factors, RNA processing, or translation
  • Examples include small molecule inhibitors of transcription factors (JQ1, a BET bromodomain inhibitor) and antisense oligonucleotides that target specific mRNAs (nusinersen, used to treat spinal muscular atrophy)

Drug Resistance and Selectivity

• Mutations in drug targets can lead to resistance by altering the binding site or affecting the target's function
  • Examples include mutations in the active site of HIV reverse transcriptase, leading to resistance to nucleoside reverse transcriptase inhibitors
• Alterations in drug metabolism can affect the concentration of the drug at the target site, leading to resistance
  • Increased expression of drug-metabolizing enzymes (cytochrome P450 enzymes) can result in faster drug clearance and reduced efficacy
• Activation of compensatory pathways can circumvent the effects of a drug, leading to resistance
  • Cancer cells may upregulate alternative signaling pathways in response to targeted therapies, leading to drug resistance and tumor progression
• Improving drug selectivity can be achieved through structure-based drug design, targeting unique features of the intended target
  • Selective inhibitors of cyclooxygenase-2 (COX-2) were developed to reduce the gastrointestinal side effects associated with non-selective COX inhibitors
• Combination therapy can be used to overcome drug resistance by targeting multiple pathways or mechanisms simultaneously
  • Combination of antibiotics with different mechanisms of action can help prevent the emergence of resistant bacterial strains

Clinical Applications

• Targeted therapies are drugs designed to specifically interact with molecular targets involved in disease pathogenesis
  • Examples include small molecule kinase inhibitors (imatinib, a BCR-ABL inhibitor used to treat chronic myeloid leukemia) and monoclonal antibodies (trastuzumab, an anti-HER2 antibody used to treat breast cancer)
• Personalized medicine involves tailoring drug therapy based on an individual's genetic profile or disease characteristics
  • Pharmacogenomics studies the influence of genetic variations on drug response, allowing for the identification of patient subgroups more likely to benefit from a particular treatment
• Drug repurposing involves identifying new therapeutic applications for existing drugs, leveraging their known safety profiles
  • Sildenafil, originally developed as an antihypertensive agent, was repurposed for the treatment of erectile dysfunction
• Companion diagnostics are tests used to identify patients who are most likely to benefit from a specific drug or to monitor treatment response
  • The HER2 gene amplification test is used to identify breast cancer patients who are candidates for trastuzumab therapy
• Adverse drug reactions can be minimized by understanding the mechanisms underlying drug-target interactions and off-target effects
  • Pharmacovigilance programs monitor the safety of drugs post-approval, allowing for the identification and management of rare or unexpected adverse events

Future Directions

• Advances in structural biology techniques (X-ray crystallography, cryo-electron microscopy) are enabling the determination of high-resolution structures of drug targets
  • These structures facilitate the rational design of new drugs with improved selectivity and potency
• Computational methods, such as virtual screening and molecular docking, are being used to identify novel drug candidates and optimize lead compounds
  • Machine learning algorithms can analyze large datasets to predict drug-target interactions and prioritize compounds for experimental validation
• Targeted protein degradation is an emerging approach that uses small molecules to induce the degradation of disease-causing proteins
  • Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that recruit target proteins to E3 ubiquitin ligases for degradation
• RNA-based therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), are being developed to modulate gene expression
  • These approaches can be used to target previously undruggable proteins or to correct genetic defects underlying diseases
• Immunotherapies harness the power of the immune system to fight diseases, particularly cancer
  • Checkpoint inhibitors (nivolumab, pembrolizumab) block inhibitory signals that prevent T cells from attacking tumor cells, enhancing the anti-tumor immune response
• Microbiome-targeted therapies aim to modulate the composition and function of the gut microbiome to treat various diseases
  • Fecal microbiota transplantation has shown promise in treating recurrent Clostridium difficile infections and is being explored for other conditions such as inflammatory bowel disease