c.+Introduction+to+Drug+Discovery+%28PPTX+-+C%29.pdf

Introduction to Drug Discovery Fred F. Farris, PhD Introduction  What is a Drug? A specific chemical entity that produces a pharmacological or physiological effect when administered to a living organism Many are relatively simple molecules, while other are large an...

Introduction to Drug Discovery Fred F. Farris, PhD Introduction  What is a Drug? A specific chemical entity that produces a pharmacological or physiological effect when administered to a living organism Many are relatively simple molecules, while other are large and complex Each drug has a specific mechanism of action that can be identified and characterized  How Do Drugs Act? Non-Specific Interactions Specific Drug Targets 1. Simple Chemical Reactions 1. Non-Protein Binding 2. Surfactant Properties a. Lipids 3. Protein Denaturation b. Nucleic Acids c. Carbohydrates 4. Osmotic Effects 2. Protein Binding 5. Selective Toxicity a. Enzymes b. Ion Channels c. Transport Proteins d. Receptors  Drug Targets Biochemical Class Target Subclass Receptors Enzymes Proteins Transport Proteins Iom Channels DNA Nucleic Acids RNA Lipids Cell Membrane Lipids Cell Surface Carbohydrates Carbohydrates Antigens and Recognition Molecules  Drug Targets Typically larger than the drug molecule itself - Often a macromolecule (Polymeric form of simple biochemical building block) Drug and targets interact via specific non-covalent bonds between functional groups There always exists an equilibrium between bound and unbloud drug to its target  Drug-Target Interactions Bond Type Dominant Character Strength (kCal/mole) Atomic and Molecular Van Der Waals 1-3 Dipoles Hydrogen Bond Dipole-Dipole 3-7 Ionic Electrostatic 1 - 50 Covlant Electron Sharing > 50  Drug-Target Interactions Binding affinity between Binding Regions drug and site, allows drug to bind temporarily and Functional Groups then release once effect Intermolecular is initiated Bonds Drug Binding Site Drug Induced Fit  Drug-Target Interactions: Van Der Waals Occurs between hydrophobic regions of the drug and the target Transient areas of high and low electron densities cause temporary dipoles  Drug-Target Interactions: Hydrogen Bonding A bond between a hydrogen atom attached to an electronegative atom on one molecule and can electronegative atom on a different molecule  Hydrogen Bonding in Water Water is the prototype molecule for H-bond formation SP3 hybridization of the central oxygen atom yields a tetrahedral molecule with electron lone pairs at two apices of the tetrahedron H-O-H bond angle is 104.45o  Drug-Target Interactions: Ionic Bond Occurs between groups having opposite charges (+ and - charges) Strength of the interaction is inversely proportional to the distance between the two charges Captopril (anti-hypertensive) ionic interaction with ACE receptor Drug Discovery Introduction  US Food and Drug Administration (FDA) Food and Drug Act of 1906 required drugs marketed intestate to comply with claimed standards for strength, purity, and quality Shirley amendment of 1912 prohibited false claims of therapeutic effects Federal Food Drug and Cosmetic Act of 1938 was passed and FDA was established Prohibits distribution and use of a new drug without prior filing of a New Drug Application (NDA) and approval of FDA  Critical Role of FDA Grant or deny permission to manufacture and distribute new product after reviewing applicant’s filed data on products, ingredients, methods of assay, quality standards, formulation and manufacturing, preclinical studies, and clinical trials on human subjects Federal Food, Drug, and Cosmetic Act is codified in Title 21 of U.S. Code of Federal Regulations (CFR), and requires a new drug to be approved by the FDA before it may be legally introduced into interstate commerce Drug Discovery/Approval Timeline  FDA Drug Approval FDA Approval of an NDA indicates: Drug product is safe for proposed use Manufacturing and control methods are appropriate Product labeling is accurate and presents sufficient information for proper use of product  Discovery and Development of Penicillin 1928 - Discovered by Alexander Fleming 1938 - Isolated by Howard Florey and Ernst Chain 1941 - Successful Clinical Trials 1944 - Commercial Availability 1945 - X-ray Structural Elucidation by Dorothy Crowfoot Hodgkin 1957 - John Sheehan Published Complete Synthesis in JACS  Analytical Instrumentation Nuclear Magnetic Resonance Felix Bloch and Edward Purcell (1940s) First Commercial Instrument (Varian) 1950 Mass Spectrometry First commercial instrument (1940s)  Modern Drug Development Collaborative Effort of: Organic and/or Medicinal Chemists Biologists Molecular Biologists/Geneticists Pharmacologists/Toxicologists Statisticians Physicians Pharmacists Others  Role of Pharmaceutical Sciences in Drug Discovery Pharmaceutics: The area that studies development, and characteristics of drug dosage forms and delivery systems Pharmacology/Toxicology: The areas that investigate the beneficial and adverse interactions between the drug and the body Medicinal Chemistry: An area that deals with the discovery or design of new therapeutic chemicals and their development into useful medicines  Growth of US Pharmaceutical Industry Major growth began during and after WW II Today discovery and development focus on understanding disease mechanisms and developing new treatment modalities Biologics is the fastest growing segment within new prescription drugs: Monoclonal antibodies Therapeutic proteins Immunotherapies Vaccines  Sources of New Drugs: Plants 270,000 known plants Historically the source of many important drugs Rauwolfia serpentine - Source of Reserpine, a tranquilizer and hypotensive drug Periwinkle (Vinca rosa) - Source of vinblastine and vincristine, chemotherapeutic agents Pacific yew tree - Source of paclitaxel, the chemotherapeutic agent Taxol  Sources of New Drugs: Animals Hormonal agents including thyroid hormone, insulin, and pituitary hormones Estrogen from pregnant mares Monkey renal tissue to prepare poliomyelitis vaccine Chick embryos to prepare mumps and influenza vaccines Vaccines from cell and tissue cultures  Sources of New Drugs: CADD (Computer Aided Drug Discovery) Target Lead Compound  Sources of New Drugs: Biotechnology Recombinant DNA and Monoclonal Antibodies Potential to produce almost any protein Human insulin, growth hormone, hepatitis B vaccine, etc. Abundant and purer vaccines New chemical and biological products Manipulations of genetic material to produce proteins  Methods of Drug Discovery Fortuitous or serendipitous discovery Random and untargeted screening of organic compounds High throughput screening: Screen 15,000 chemical compounds per week , utilizing 10 - 20 biologic assays Utilize chemical libraries - combinatorial chemistry  Lead Compound A prototype compound that has a fundamental desired pharmacological activity A compound that will be modified structurally, to achieve optimal activity and minimal toxicity Modifications made to the lead compound can Morphine reveal the molecular features that are essential for activity and that produce toxicity Example: Lead compound for opioids - Morphine Methadone Drug Development  Goal Drug A drug that: Produces the specifically desired effect Can be administered by the most desired route, at a minimal dose, and at most convenient frequency Has an optimal onset and duration of effect Exhibits no side-effects Is eliminated from the body efficiently, completely, and without residual effect Is pharmaceutically elegant and stable  Lead Optimization Scientists can influence the properties of the lead compound by chemical modifications in the structure The aim is to generate analogs of the initial lead with improved potency, reduced off-target activities, and desirable physicochemical properties In the end, the best performing compound is chosen as a potential drug to enter preclinical development Causes GI Bleeding Prodrug - No GI Bleeding Salicylic Acid Aspirin  Structure-Activity Relationships (SAR) Relationship between the chemical structure of a molecule and its biological or physiological activity SAR is related to the functional groups on the drug molecule and how these interact with specific groups at the biological site of action Can be tested by modifying regions of the drug molecule and measuring pharmacological activity after each modification Example of SAR: Analgesia of Opioids  Pharmacophore Structural features including relative position in space of important functional groups directly responsible for activity Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the active conformation (3D structural feature) Important to drug design and discovery Analgesic Pharmacophore for Opioids Pharmacophore triangle  Pharmacophore of Morphine for Analgesic Activity Phenolic Group Aromatic Ring 38 Tertiary Amine Morphine  Prodrug A compound that requires metabolic transformation after administration to produce the desired pharmacologically active compound Prodrugs may be preferentially desired for improved: Solubility Absorption Stability Prolonged release  Lead Optimization Strategies Purpose Strategy To increase activity 1. Vary alkyl substituents (potency) 2. Vary aryl substituents To reduce dose levels 3. Extension To increase selectivity 4. Chain modification To reduce side effects 5. Ring modification 6. Isosteres 7. Simplification 8. Rigidification  Strategy 1: Variation in Alkyl Substituents An alkyl group in the lead compound may interact with a hydrophobic region on the Target via Van Der Waals forces Vary the length and/or bulk of the group to affect the binding interaction Hydrophobic Pocket  Strategy 2: Variation in Aryl Substituents If the compound contains an aromatic ring, the position of substituents can be varied to find better binding interactions, resulting in increased activity Weak H-Bond Strong H-Bond Binding Region (H-Bond) Binding Region For Y substituent  Strategy 3: Extension To explore target binding site for further binding regions to achieve additional binding interactions, functional groups may be extended or added Extra Unused Functional Binding Group Region Added Binding Regions Binding Groups  Strategy 4: Chain Modification Useful if a chain is present connecting two binding groups Vary length of chain to optimize interactions  Strategy 5: Ring Modification To improve overlap of binding groups with their binding regions  Strategy 6: Isosteres and Bio-isosteres Bio-isostere: a group that can be used to replace another group while retaining the desired biological activity  Strategy 7: Simplification Retain pharmacophore and remove any unnecessary functional groups and rings  Strategy 8: Rigidification Bonds with ring systems are locked and cannot rotate freely Test rigid structures to see wich ones have retained active conformation  Questions 1. (T/F) Binding is a process of interaction between a drug and its target 2. (T/F) Drug targets have simple and smaller structures compared to drugs 3. (T/F) Most drugs are in equilibrium between being bound and unbound to their target 4. (T/F) Binding affinity can determine the strength of binding between a drug and its target 5. (T/F) Functional groups of a drug can interact with the target by binding to the active site of the target 6. (T/F) A currently used drug cannot be a lead compound 7. (T/F) High-throughput screening (HTS) can be used to identify a lead compound  Question (MC) What is meant by a lead compound in Medicinal Chemistry? (Choose all that apply) A. A drug containing the element lead B. A leading drug in a particular area of medicine C. A compound that acts as the starting point for developing better drugs D. A compound that has some desired biological activity by binding the chosen target but still has a suboptimal structure Biological Characterization And Preclinical Trials  Pharmacology Understand how drugs work and how best to utilize them to optimize patient therapy Three Major Divisions: Pharmacokinetics - Drug Movement and optimization of therapy Pharmacodynamics - Mechanisms of drug action  Pharmacology Absorption Distribution Metabolism ADME Excretion Elimination - Metabolism, and Excretion Disposition - Distribution, Metabolism, and Excretion  Pharmacodynamics The study of the fundamental or molecular interactions between the drug and the body constituents which result in the observed pharmacological responses  Pharmacogenomics The field of research that studies how a person's genes affect how he or she responds to medications  Toxicology The study of the adverse effects of chemicals on living organisms and the analysis of factors that influence these effects Preclinical drug safety studies are undertaken to determine: Acute and chronic toxicity Specific organ toxicity Dose-response relationships Gender and reproductive toxicity Carcinogenic and genotoxic potential Clinical Trials Phases of Clinical Trials Drug Effects Drug Effect in a Population Sample  Drug Effects Locally Acting Drugs Drugs that act at the site of administration Systemically Acting Drugs Drugs that act remote from the site of administration Therapeutic & Toxic Blood Levels of Drugs  ED50, TD50, LD50 & Therapeutic Index ED50 (Effective Dose 50): The dose that will produce the desire therapeutic effect in 50% of the subjects to which it is administered TD50 (Toxic Dose 50): The dose that produces the specified toxic endpoint in 50% of the subjects to which is it administered LD50 (Lethal Dose 50): The dose that produces lethality in 50% of the subjects to which it is administered Therapeutic Index = [TD50]/[ED50] Therapeutic Indices of Drugs  Questions (2) 1. (T/F) The purpose of lead optimization is to improve potency and reduce off-target activity by chemical modification 2. T/F) One of the common strategy for lead optimization is the analysis of structure-activity relationship (SAR) 3. (T/F) SAR is the relationship between the structure of drug target (binding site) and the activity of a drug 4. (T/F) SAR can give idea of what functional groups are not important for biological activity 5. (T/F) Pharmacophore represents a real molecule 6. (T/F) Pharmacophore defines important structural features, that are directly responsible for activity, with their relative 3D position