drug discovery

• Medicine

  Any substance/chemical which is taken in prescribed controlled quantity for treating the physiological/mental/psychological abnormality of the human (pathological state)
• Discovery phase


  Identification of a new molecule/chemical entity as a potential therapeutic agent
• Development phase


  Compound is tested for safety and efficacy for one or more clinical indications in suitable formulations and dosage form
• We need new medicines due to unmet medical need, new diseases, low efficacy, side effects, downstream health costs, cost of therapy, costs to individual country, and to sustain industrial activity
• Early drug discovery


  • Willow bark and salicylic acid
  • Doctrine of Signatures
• In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery
• Now we know diseases are controlled at molecular and physiological level, and the shape of a molecule at atomic level is well understood
• History of medicine discovery


  • Pre 1919: Herbal Drugs, Accidental discoveries
  • 1920s, 30s: Vitamins, Vaccines
  • 1940s: Antibiotic Era, R&D Boost due to WW II
  • 1950s: New technology, Discovery of DNA
  • 1960s: Breakthrough in Etiology
  • 1970s: Rise of Biotechnology, Use of IT
  • 1980s: Commercialization of Drug Discovery, Combinatorial Chemistry
  • 1990s: Robotics, Automation
• Change in medicine discovery over time


  • Pre 1919: Natural sources, Limited possibilities, Small scale, Not purified/standardized/tested, Limited administration, No controls, No idea of mechanisms
  • The 1990s and 2000: Synthetic source, Unlimited possibilities, Prepared by companies, Massive scale, Highly purified/standardized/tested, World-wide administration, Tight legislative control, Mechanisms partly understood
• Who discover and develop medicine?


  • Universities
  • Independent research groups
  • Pharmaceutical companies
• Approaches to medicine discovery


  • Classical pharmacology (phenotypic drug discovery)
  • Modern medicine discovery process (reverse pharmacology, target-based drug discovery)
• Approaches to medicine discovery

  • Historical
  • Study disease process
  • Study biochemical/physiological pathway
  • Design to fit known structurally identified biological site
  • By chance (serendipity)
  • Genomics
• Process of Medicine Discovery and Development


  1. Target Identification

  2. Target Validation

  3. Lead Identification

  4. Lead Optimization

  5. Preclinical and clinical studies
• Choosing a Disease

  Pharmaceutical companies are commercial enterprises, so they tend to avoid products with a small market or that would be consumed by individuals of lower economic status. An orphan drug is a pharmaceutical agent developed specifically to treat a rare medical condition.
• Hypothesis generation

  Based on in-house experimentation, published materials or serendipitous, the hypothesis links to the disease progression pathway, and the drug molecule should be able to modify this pathway
• Target base drug discovery is also known as reductionist approach, where a single biological target is identified (and validated) as a primary cause of disease
• Drug Target


  Specific macromolecule, or biological system, which the drug will interact with and bind
• Strategies to find new medicines targets


  • Conventional strategies: Analysis of pathophysiology, Analysis of MOA of existing drugs
  • New strategies: Disease genes, Disease-modifying genes
• Medicine targets

  • Enzyme (Inhibitor - reversible or irreversible)
  • Receptor (Agonist or antagonist)
  • Nucleic acid (Intercalator, modifier, substrate mimic)
  • Ion channels (Blockers or openers)
  • Transporters (Uptake inhibitors)
• Proteomics is important as disease processes become manifest at the protein level, and most drugs act at this level
• Genomics


  The study of genes and their function, including mapping genes and sequencing DNA
• Bioinformatics


  A branch of molecular biology that involves extensive analysis of biological data using computers, for the purpose of enhancing biological research, e.g. target identification, computer screening of chemicals
• Target validation

  To prove that manipulating the selected molecular target can provide therapeutic benefit for patients, by showing it is critical in the disease process
• Sources of medicines (hits and lead molecules)

  • Animal
  • Plants
  • Inorganic
  • Synthetic (Chemicals, Biological, Biotechnology)
• Genesis of medicines

  • Random screening
  • Extraction of active principles from natural sources
  • Molecular modification of known drugs
  • Serendipity
  • Selection or synthesis of soft drugs
  • Drug latentiation /Prodrug
  • Rational design of drugs
• Hits identification


  Those small molecules that are identified at this initial stage have affinity for the biological target, but little else is known about them
• Sources of Hit/Lead Molecules

  • Papaver somniferum: Morphine
  • Atropa belladona: Atropine
  • Rauwolfia serpentina: Reserpine
  • Digitalis lanata: Digoxin
  • Strychnos toxifera: d- TC
  • Pilocarpus microphyllus: Pilocarpine
  • Salix alba (Willow bark): Aspirin
  • Bark of Yew tree: Paclitaxel
  • Cinchona tree: Quinine
• Finding the Hits/Leads

  • Screening Natural Products
  • Screening synthetic banks – High throughput screening
  • Molecular modifications/ manipulation
• Sources of Hit/Lead Molecules
• Sources of Hit/Lead Molecules

  • Papaver somniferum
  • Digitalis lanata
• Screening Natural Products

  Finding the Hits/Leads
• Screening synthetic banks – High throughput screening

  1. Pharmaceutical companies have prepared thousands of compounds

  2. These are stored (in the freezer!), cataloged and screened on new targets as these new targets are identified

  3. Screening of drug target against selection of chemicals

  4. Identification of highly target specific compounds
• Molecular modifications/ manipulation

  1. A well established chemical substance of known biological activity is considered as a lead or prototype

  2. Some of these modifications have been made with the purpose of exploring the side effects of known drugs
• Molecular modeling/modification


  1. Design structure which is similar to existing lead, but different enough to avoid patent restrictions

  2. Enhance a side effect

  3. Use structural similarity to a natural ligand
• Serendipity


  Valuable discoveries accidentally, luckily or suddenly by Pharmacists, Chemists, Physicians & other investigators
• Serendipity


  • Penicillin discovery
  • Development of Sildenafil to treat erectile dysfunction
• Computer-Assisted Drug Design (CADD)

  If one knows the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly-fitting ligand
• Combinatorial chemistry

  Systematic and repetitive covalent connection of set of different building blocks of varying structures to each other to yield a large array of diverse molecular entities
• Biotechnology

  • Therapeutic agents produced by biotechnology rather than conventional synthetic chemistry are called Biopharmaceuticals
  • Involve the use of recombinant DNA technology /genetic engineering to produce large amount of hormones like insulin, growth hormone
• Genetic medicines

  • Synthetic oligonucleotides are developed to target defined sites of the DNA sequence
  • Genes (double stranded DNA) blocks transcription
  • Messenger RNA (antisense therapy) blocks disease related protein synthesis
  • The oligonucleotides are used as treatment for cancer and viruses without harming healthy tissues