Drug Discovery and Development Process - Suli Drug Discovery and Development Process Research team formed

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  • Drug Discovery and Development Process

    Research team formed and objectives test Novel chemical synthesis

    Chemicals tested for efficacy and safety in test tubes and animals. Results used to choose drug candidate

    Formulation, stability scale- up synthesis, chronic safety in animals

    Company file Investigational New Drug application with FDA

    Clinical studies: Phase I, II, and III

    Company files New Drug

    Application (NDA)

    FDA reviews NDADrug is approved for marketing

  • Screening(to(obtain(a(hit(compound ((




    Clinical(studies( phase(I,(II,(and(



  • Drug Design • Drug design is an integrated developing discipline which

    means era of ‘tailored drug’.

    • It involves the study of effects of biologically active compounds on the basis of molecular interactions in terms of molecular structure or its physicochemical properties involved.

    • It studies the processes by which the drug produce their effects, how they react with the protoplasm to elicit a particular pharmacological effect or response how they are modified or detoxified, metabolized or eliminated by the organism.

  • • The biological activity may be “positive” as in drug design or “negative” as in toxicology.

    • Drug design involves either total innovation of a molecule or an optimization of already available one.

    • The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient.

    • In the most basic sense, drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it.

    • Drug design frequently but not necessarily relies on computer modelling techniques. This type of modelling is often referred to as computer-aided drug design.

  • Pharmacokinetics of Drug Design

    • Drugs must be polar - to be soluble in aqueous conditions to interact with molecular targets

    • Drugs must be ‘fatty’ - to cross cell membranes to avoid rapid excretion

    • Drugs must have both hydrophilic and lipophilic characteristics

  • Traditional vs. Contemporary Approaches

  • Traditional vs. rational drug design • Traditional is the origin of discovery from natural and accidental


    • It was not targeted, but advancement in the pharmaceutical sciences changed them to the systemized modern drug discovery.

    • Traditional discoveries were through random discovery, trials, ethnopharmacology, serendipity, and classical pharmacology

    Examples of traditional approach, such as using cinchona bark (quinine) to reduce fever, licorice roots in sore throats and stomach ulcer, penicillin, etc.

  • Rational drug design

    Developing molecules as a ligand either for targets known the structure and function or the structural information not known; however, it has predefined properties and information can be taken from global gene expression data.

  • Rational drug design

    It can be divided in to 1. Ligand based drug design a. QSAR b. Pharmacophore investigation 2. Structure based drug design a. Docking b. De novo drug design

  • Hit Compound • Once a promising drug target has been identified, researchers

    aim to identify molecules that can interact with the target to produce desired biological effects.

    • A hit compound is a molecule that shows the desired type of activity in a screening assay.

    • It is important to develop pharmacologically relevant screening assays for hit discovery and for the subsequent hit- to-lead selection process.

  • Lead compound • Lead compound is a prototype compound that has the desired

    biological or pharmacological activity but may have many undesirable characteristics.

    • Providing lead compounds (via traditional medicines, natural products, biological macromolecules, compound libraries, computational chemistry, etc.)

    • Lead compounds are selected from a collection of hits by refining the screening criteria to enable the selection of the most promising molecules for further development. The secondary assays employed for lead selection may screen for off-target effects as well as physicochemical and ADME (absorption, distribution, metabolism and excretion) characteristics.

  • 1. Where is the starting point of drug discovery?

    2. What are the essential causes of the drugs fail to reach the clinic?

    3. What are the characteristics of good target? 4. What are the types of target?

  • Good target characteristics

    • Plays a critical role in health-related issues • Modulated without killing human or serious

    harmful effect • The structure of the target should be unique • Well defined molecular structure of the target • Modulate through designing small molecule

  • • Target sites are enzymes, receptors, ion channels, DNA, RNA, proteins, viral surface proteins, etc.

    • What are the most targets of the current drugs?

    • Many experts believe that “without a well-validated targets, pharmaceutical companies unable to maintain current level of profitability” therefore, it’s one of the stressing issues in the R&D.

    • The process of the design of drugs typically involves understanding the character of targets (e.g. enzyme, cell, tissues, etc) related to the disease.

  • H to L LD and LO Hit Lead Candidate

    H to L: focus on target potency and selectivity; defined in vitro properties profile. LD: focus on identifying a novel compound with the desired activity in vitro and vivo, with refinement of physical properties. LO: focus on fine tuning ADMET properties to identify one or more preclinical development candidates.

  • Hit to Lead evolved in the 1990’s to address a growing problem with drug candidate failures

    • In the “old” days—

    Ø Focus only on potency; SAR advancement emphasized potency

    with minimal consideration of other attributes Ø Result: compounds with poor bioavailability, high

    clearance, high risk off-target effects, low solubility and low dissolution properties, clinical trial failures

    Ø Success rate of drug candidates from candidate nomination to market: 4-6%

    The modern day H to L process was developed to identify and eliminate poor quality leads right up front

  • • Different screening strategies can be applied

    1. Literature 2. HTS 3. Phenotypic screening 4. Computer Aided Drug Design A. Structure-based drug design B. Ligand-based drug design C. Fragment screening D. Virtual screening (Docking and Scoring)

  • 1. The source of the hit • Natural product leads tend to be structurally complex

    2. The nature of the screening library • Historical compound collections are a legacy of past discovery programs;

    poorly managed DMSO solvated libraries may show considerable degradation

    3. The quality and precision of the screening method • Noisy or low resolution screens introduce high false positives

    4. The nature of the molecular target • Molecular targets designed to interact with lipoidal ligands/substrates

    tend to favor lipophilic hits; protein-protein interfaces favor structurally complex (high MW) ligands

  • • Molecular weight (MW) • Molecular volume and dimensions • Calculated partition coefficient (clogP) • Rotatable bonds • Total polar surface area (tPSA) • Aromatic rings • Hydrogen bond donors and acceptors • Physical properties influence the behavior of a compound in

    the tissue and the effectiveness of the treatment • Properties for most marketed drugs fall within a well-defined

    range of values • Lipinski’s ‘Rule of 5’ used to define potential drug candidates

  • Lipinski’s Rule of Fives

    It also known as the Pfizer's rule of five or simply the Rule of five (RO5) is a rule of thumb to evaluate drug likeness or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilic molecules.

  • • The rule describes molecular properties important for a drug's pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion("ADME"). However, the rule does not predict if a compound is pharmacologically active.

    • The rule is important to keep in mind during drug discovery when a pharmacologically active lead structure is optimized step-wise to increase the activity and selectivity of the compound as well as to insure drug-like physicochemical properties are maintained as described by Lipinski's rule. Candidate drugs that conform to the RO5 tend to have lower attrition rates during clinical trials and hence have an increased chance of reaching the market

  • Components of the rule :

    • Lipinski's rule states that, in general, an orally