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    Drug Design Bioinformatics

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    The document discusses drug design and related computational methods. It covers topics like virtual screening, molecular docking, structure activity relationships, and quantitative structure activity relationships. These methods are used to identify potential drug candidates and optimize their properties through computational modeling and simulations.

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    Drug Design Bioinformatics

    Uploaded by

    Ideen
    21 views26 pages
    The document discusses drug design and related computational methods. It covers topics like virtual screening, molecular docking, structure activity relationships, and quantitative structure activity relationships. These methods are used to identify potential drug candidates and optimize their properties through computational modeling and simulations.

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    The document discusses drug design and related computational methods. It covers topics like virtual screening, molecular docking, structure activity relationships, and quantitative structure activity relationships. These methods are used to identify potential drug candidates and optimize their properties through computational modeling and simulations.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    21 views26 pages

    Drug Design Bioinformatics

    Uploaded by

    Ideen
    The document discusses drug design and related computational methods. It covers topics like virtual screening, molecular docking, structure activity relationships, and quantitative structure activity relationships. These methods are used to identify potential drug candidates and optimize their properties through computational modeling and simulations.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 26

    DRUG DESIGN

    Introduction to Drug Design


     Drug discovery is the process through which potential new therapeutic entities are identified,
    using a combination of computational, experimental, translational, and clinical models .
     Despite advances in biotechnology and understanding of biological systems, drug discovery
    is still a lengthy, costly, difficult, and inefficient process with a high attrition rate of new
    therapeutic discovery.
     Drug design is the inventive process of finding new medications based on the knowledge of a
    biological target. In the most basic sense, drug design involves the design of molecules that
    are complementary in shape and charge to the molecular target with which they interact and
    bind.
     Drug design frequently but not necessarily relies on computer modeling techniques and
    bioinformatics approaches in the big data era. In addition to small molecules,
    biopharmaceuticals and especially therapeutic antibodies are an increasingly important class
    of drugs and computational methods for improving the affinity, selectivity, and stability of
    these protein-based therapeutics have also gained great advances .
     CADD is an exciting and continually
    evolving area that leverages new data and
    methods to provide approaches that tackle
    the ever-changing needs of drug discovery.
    The scope continues to grow, and
    applications now span the whole drug
    discovery process.
     The availability of experimental data for
    model building for multiple endpoints or
    selectivity targets enables CADD to tackle
    the needed multidimensional optimization
    challenge, and a combination of models for
    the different endpoints can be used, together
    with a variety of methods
    Historical Perspective
     Drug Discovery in modern times straddles three main periods. The first notable period can be traced to the nineteenth
    century where the basis of drug discovery relied on the serendipity of the medicinal chemists.
     The second period commenced around the early twentieth century when new drug structures were found, which
    contributed for a new era of antibiotics discovery. Based on these known structures, and with the development of
    powerful new techniques such as molecular modelling, combinatorial chemistry, and automated high-throughput
    screening, rapid advances occurred in drug discovery towards the end of the century. The period also was
    revolutionized by the emergence of recombinant DNA technology, where it became possible to develop potential drugs
    target candidates.
     With all the expansion of new technologies and the onset of the "Omics" revolution in the twenty-first century, the third
    period has kick-started with an increase in biopharmaceutical drugs approved by FDA/EMEA for therapeutic use.
     FDA Approval refers to the list of drugs approved by the Food and Drug Administration (FDA) for sale in the
    United States. New drugs receive extensive scrutiny before FDA approval in a process called a New Drug Application
    or NDA.
     Failure Modes and Effects Analysis (FMEA) is proactive method for evaluating a drug product to identify where and
    how it might impact and to assess the relative impact of different failures, in order to identify the parts of the process
    that are most in need of change.
    MODERN METHODS OF DRUG DISCOVERY
    Drug discovery process beginswith a disease (rather than a treatment)
    Use disease model to pinpointrelevant genetic/biologicalcomponents (i.e. possible drug targets)
    DISEASE → Genetic/Biological target
    ↓
    Discovery of a “LEAD” molecule
    o Design assay to measure function of target
    o Use assay to look for modulators of
    target’s function
    ↓
    High Throughput Screen [HTS]
    o To identify “hits” (compounds with binding in low nM to low µM range)

     
     
     
     
     
     
     

     
    Small Molecule Hits
    ↓
    Manipulate Structure to Increase Potency
    i.e. decrease Ki to low nM affinity
    ↓
    Optimization of lead molecule into candidate drug
     
    Fulfillment of required Pharmacological properties [Potency, absorption,
    bioavailability, metabolism, safety]
    ↓
    Clinical Trials
    Drug Design
    Molecular Docking ( MD )

    Virtual Screening ( Structure or Ligand based )

    Quantitative Structure Activity Relationship ( QSAR )


    VIRTUAL SCREENING
     [Structure-based Approach]
     To identify potential lead compounds from large dataset
     Known structures of organic compounds
     Libraries of Virtual Compounds
     Programs calculate affinity for protein
     Narrow down to small number of possibilities
     Surface Representation that efficiently represents the docking
    surface & identifies the regions of interest [cavity & protrusions]
     Surface Matching that matches surfaces to optimize a binding score
    MOLECULAR DOCKING
    Molecular
     docking
    One of the most frequently used methods in structure- based drug design

    Due to its ability to predict the binding-conformation of small molecule ligands
    to appropriate target binding site.
    Characterisation of binding behaviour plays an important role in rational design

    of drugs as well as to elucidate fundamental biochemical processes.

     
    Docking can be done between
    • Protein-Ligand
    • Protein-Protein
    • Protein-Nucleotide
     
    Protein may serve as the “LOCK” & Ligand
    as the “KEY”
    Each ligand has particular binding site to its
    protein partner.
    MOLECULAR DOCKING: APPLICATIONS
     Virtual Screening [Hit Identification]
     Docking with a scoring function can be used to quickly screen large database of potential
    drugs in silico to identify molecules that are likely to bind to protein target of interest.
     Bioremediation
     Proteinligand docking can also be used to predict pollutants that can be degraded by
    enzymes
     To study geometry of a particular complex [Rational Design of Drugs]
     Identification of ligand’s correct binding geometry in binding site.
     Prediction of affinity binding
     For predicting protein-protein interactions
    Softwares for Molecular Docking
    SAR [STRUCTURE ACTIVITY RELATIONSHIP]
    Predicting Biological Activity From Structure

    Traditional
     practices of medicinal chemistry which try to modify the effect or the
    potency (i.e. activity) of bioactive chemical compounds by modifying their chemical
    structure.
    Medicinal chemists use the techniques of chemical synthesis to insert new chemical

    groups into the biomedical compound and test the modifications for their biological
    effects.
    Enables identification & determination of chemical groups responsible for evoking a

    target biological effect in organism.
    Basic assumption for all molecule based hypotheses is that similar molecules have

    similar activities.
    .
     
    The
     underlying problem is therefore how to define a small difference on a
    molecular level, since each kind of activity [e.g. reaction ability,
    biotransformation ability, solubility, target activity], might depend on another
    difference.
    In general, one is more interested in finding strong trends.

    Created hypotheses usually rely on a finite number of chemical data.

    Thus, the induction principle should be respected to avoid overfitted

    hypotheses and deriving overfitted and useless interpretations on
    structural/molecular data.
    The SAR paradox refers to the fact that it is not the case that all similar

    molecules have similar activities.
    STRUCTURE ACTIVITY RELATIONSHIP [SAR]
     Drug design is an iterative process which begins with a compound that displays an
    interesting biological profile and ends with optimizing both the activity profile for the
    molecule and its chemical synthesis.
     Theprocess is initiated when the chemist conceives a hypothesis which relates the
    chemical features of the molecule (or series of molecules) to the biological activity.
     Without a detailed understanding of the biochemical processes responsible for activity,
    the hypothesis generally is refined by examining structural similarities and differences for
    active and inactive molecules.
     Compounds are selected for synthesis which maximize the presence of functional groups
    or features believed to be responsible for activity.
     A Quantitative Structure Activity Relationship (QSAR) can then be utilized to help
    guide chemical synthesis..
    QUANTITATIVE STRUCTURE-ACTIVITY
    RELATIONSHIP [QSAR]
    Sometimes QSPR: Quantitative Structure-property Relationship
    SAR
     Method later refined to build mathematical relationships between a chemical structure
    and its biological activity, known as Quantitative Structure-Activity Relationships (QSAR).
    Process by which chemical structure is quantitatively correlated with a well defined process,

    such as biological activity or chemical reactivity.
    Biological activity can be expressed quantitatively as in the concentration of a substance

    required to give a certain biological response.
    Additionally, when physico-chemical properties or structures are expressed by numbers, one

    can form a mathematical relationship, or quantitative structure activity relationship, between
    the two.
    Mathematical expression can then be used to predict biological response of other chemical

    structures.
    QSAR

    QSAR
     represent an attempt to correlate structural or property descriptors of
    compounds with activities.
    ● These physicochemical descriptors, which include parameters to account for
    hydrophobicity, topology, electronic properties, & steric effects
    ● Determined empirically or, more recently, by computational methods.
    Activities used in QSAR include chemical measurements & biological assays.

    QSAR currently are being applied in many disciplines, with many pertaining to

    DRUG DESIGN and ENVIRONMENTAL RISK ASSESSMENT
    To
     relate the biological activity of a series of compounds to their physicochemical
    parameters in a quantitative fashion using a mathematical formula.

    Requirements

    Quantitative
     measurements for biological and physicochemical properties-
    Hydrophobicity of the molecule

    Hydrophobicity of substituent

    Electronic properties of substituent

    Steric properties of substituent

    3D-QSAR
     Structural descriptors are of immense importance in every QSAR model.
     Common structural descriptors are pharmacophores and molecule fields.
     Superimposition of the molecules is necessary.
     PHARMACOPHORE
    •An abstract description of molecular features that are necessary for molecular recognition
    of a ligand by a biological macromolecule.
    •A pharmacophore model explains how structurally diverse ligands can bind to a common
    receptor site.
    •Pharmacophore models can be used to identify through de novo design or virtual
    screening novel ligands that will bind to the same receptor.
    3D-QSAR ASSUMPTIONS
    The
     effect is produced by modeled compound and not it’s metabolites.
    The proposed conformation is the bioactive one.

    The binding site is the same for all modeled compounds.

    The biological activity is largely explained by enthalpic processes.

    ○ Entropic terms are similar for all the compounds.
    The system is considered to be at equilibrium, and kinetics aspects are usually

    not considered.
    Pharmacokinetics:

    ○ Solvent effects, diffusion, transport are not included.
    Source-
    ○Pevsner J. Bioinformatics & Functional Genomics
    ○Ghosh Z. & Bibekanand M. Bioinformatics:
    Principles & Applications
    Thank you

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