Informatics in Drug Discovery - evqfm.com.br ?· Phases of Drug Discovery Enabling Science & Technology…

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  • Informatics in Informatics in Drug DiscoveryDrug Discovery

    Tudor I. OpreaDivision of Biocomputing

    University of New Mexico School of Medicinetoprea@salud.unm.edu

    The University of New MexicoDivision of BIOCOMPUTINGCopyright Tudor I. Oprea, 2008. All rights reserved

  • OutlineOutline Phases of Drug Discovery Target Identification

    What is Bioinformatics?

    Hit Identification What is Cheminformatics?

    Lead Identification The GPR30 agonist; systems chemical biology

    Lead Optimization Structure-based design against Influenza

    The Importance of Accurate Information

  • PalestrantePalestrante Palestra: The first definition of the word comes from the ancient times (ant.):

    lugar para exerccios de ginstica na Grcia e em Roma. (Place for the practice of exercises and gymnastic in Greece and Rome)

    The "Boxer Vase" from Hagia Triada in Crete So Palestrante is a practitioner of exercises

    in this case, of Speech and Mind

  • Phases of Drug DiscoveryPhases of Drug Discovery

    Enabling Science & Technology Emerging Technologies

    Predictive ADME/Tox, Safety Assessment Front-loading Risk

    Therapeutic Input Clinical Insights

    Stringent Criteria

    Clinical CandidateTarget Lead

    Target Identification

    HitIdentification

    Lead & ProbeIdentification

    Concept Testing Launch

    Develop-ment for launch

    Lead/Probe optimization

    File for:eINDIND

    Receive:NDA

  • Preclinical Drug Discovery ParadigmPreclinical Drug Discovery Paradigm

    TargetsTargets LeadsLeadsIdenti-fication

    Vali-dation

    Design

    MakeTest

    GenomeProteomeDisease AreaBiol. Effects

    Hit IDOngoing TV Fast-followersIntellectual Property coverageCandidate DrugsCandidate Drugs

    BioinformaticsBioinformatics CheminformaticsCheminformatics

    Medical InformaticsMedical Informatics

  • Target Identification

    Hit Identif.

    Lead Identif.

    Lead optim.

    Clinical Candidate

    ProductionIdentification

    Human genetics

    Mouse genetics

    Target Identification in Preclinical DiscoveryTarget Identification in Preclinical Discovery

    ValidationThe key in target identification is mass production of pure protein for structural studies

  • What is Bioinformatics?What is Bioinformatics? Historically, bioinformatics was related to sequence

    analysis for genes & proteins It tried to find patterns in multiple seq., and understand how

    sequence information relates to genes, proteins, cellular substructures (organelles), cells and tissues, as well as whole (micro)organisms.

    Bioinformatics is the field of science in which biology, computer science, and information technology merge to form a single discipline.

    Its ultimate goal is to enable the discovery of new biological insights as well as to create a global perspective from which unifying principles in biology can be discerned

  • Human Genome MapHuman Genome Map

    Use this website to search the human genome. No prior experience required.

    http://www.ncbi.nlm.nih.gov/mapview/map_search.cgi

  • Query: Query: Color BlindnessColor Blindness

    Two hits on chromosomes 7 and X (opsin)

  • Continuing the searchContinuing the search We searched GenBank for human opsin

    and found >150 hits. We selected NT_025965 (Homo sapiens chromosome X) We then searched for opsin 1 in the hitlist, and

    found a mRNA, that was in turn translated into the following protein sequence:

    MAQQWSLQRLAGRHPQDSYEDSTQSSIFTYTNSNSTRGPFEGPNYHIAPRWVYHLTSVWMIFVVTASVFTNGLVLAATMKFKKLRHPLNWILVNLAVADLAETVIASTISIVNQVSGYFVLGHPMCVLEGYTVSLCGITGLWSLAIISWERWLVVCKPFGNVRFDAKLAIVGIAFSWIWSAVWTAPPIFGWSRYWPHGLKTSCGPDVFSGSSYPGVQSYMIVLMVTCCIIPLAIIMLCYLQVWLAIRAVAKQQKESESTQKAEKEVTRMVVVMIFAYCVCWGPYTFFACFAAANPGYAFHPLMAALPAYFAKSATIYNPVIYVFMNRQFRNCILQLFGKKVDDGSELSSASKTEVSSVSSVS

    This sequence was submitted to BLAST

  • BLAST / PDB ResultsBLAST / PDB Results Our query was limited to PDB (Protein DataBank) Putative conserved domain (7 TM) has been detected:

    Five seq. (3 proteins from the opsin family, 2 fragments) were identified:

  • 1F881F88: X: X--ray structure of ray structure of bovine bovine rhodopsinrhodopsin

    Front view (left) and trans-membrane view (right) of the prototype for 7-TM protein models for GPCRs (G-protein coupled receptors)

    e.c.

    i.c.

    t.m.

    GPCRs are targets to ~35% of the known drugs

  • Statistical distribution of Statistical distribution of AffymetrixAffymetrix U133U133--A A gene chip probes produced by gene chip probes produced by BPQsBPQs after after

    18 hr incubation with MCF18 hr incubation with MCF--10A cells. 10A cells.

    This analysis provided Scott Burchiel with a small subset of genes that could be analyzed in more detail. Experiments indicated that 3,6-BPQ induces dioxin-response elements more than 1,6-BPQ.

    3,6-BPQ1,6-BPQ

    S.W. Burchiel et al., Toxicol. Applied Pharmacol 2007, 221:203-214

  • Top Genes Expressed after BPQ ExposureTop Genes Expressed after BPQ Exposure

    The University of New MexicoDivision of BIOCOMPUTING

    Browse Pathways for free at Biocarta.com

    172816q22.1 NQO1 NAD(P)H dehydrogenase, quinone 1210519_s_at

    864410p15-p14 AKR1C3 Aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)209160_at

    15452p21 CYP1B1 cytochrome P450, family 1, subfamily B, polypeptide 1202436_s_at

    164610p15-p14 AKR1C2

    Aldo-keto reductase family 1, member C2 (dihydrodioldehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III)

    211653_x_at

    164610p15-p14 AKR1C2

    Aldo-keto reductase family 1, member C2 (dihydrodioldehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III)

    209699_x_at

    164510p15-p14 AKR1C1

    Aldo-keto reductase family 1, member C1 (dihydrodioldehydrogenase 1; 20-alpha (3-alpha)-hydroxysteroid dehydrogenase)

    216594_x_at

    164510p15-p14 AKR1C1

    Aldo-keto reductase family 1, member C1 (dihydrodioldehydrogenase 1; 20-alpha (3-alpha)-hydroxysteroid dehydrogenase)

    204151_x_at

    LocusLink

    ChromosomeGeneDescriptionProbe

    S.W. Burchiel et al., Toxicol. Applied Pharmacol 2007, 221:203-214

  • TryptophanTryptophan Metabolism (KEGG)Metabolism (KEGG)

    http://www.biocarta.com/pathfiles/tryptophanPathway.asp

    CYP1B1

  • CYP1B1 CYP1B1 Homology Homology

    ModelModelBuilt from X-ray structure of CYP2B4

    Partially optimized with 3,6-BPQ

    O

    O

    Benzo[a]pyrene-3,6-dioneCAS # 3067-14-9

    The University of New MexicoDivision of BIOCOMPUTING

  • High Throughput Synthesis and Screening

    Synthetic Compounds Natural Products

    Target Identification

    Hit Identif.

    Lead Identif.

    Lead optim.

    Clinical Candidate

    Modern Technologies in Preclinical DiscoveryModern Technologies in Preclinical Discovery

  • Compound managementCompound management

    Handles both liquids & solidsRobots designed for fast reformatting & subsetting (cherry picking)Cheminformatics-based selection for diversity

  • From single compound synthesis to From single compound synthesis to combinatorial chemistrycombinatorial chemistry

    Courtesy of Thomas Khler

  • Compound storage is fully automated

  • What is What is CheminformaticsCheminformatics?? Molecular models are widely-used in biosciences ranging

    from analytical chemistry & biochemistry to immunology & toxicology

    Cheminformatics integrates data via computer-assisted manipulation of chemical structures

    Chemical inventory & compound registration are vital to cheminformatics, but it is their combination with other theoretical tools, linked to physical (organic) chemistry, toxicity, etc. that brings unique capabilities in the area of bioactivity discovery.

    Other names used by different people that relate to cheminformatics and computational chemistry: computer-aided drug design; quantum dynamics; biopolymer modeling; molecular / chemical diversity; virtual screening; etc...

  • 1 1 60 0 01 2 60 0 01 3 10 1 91 4 5 2 2. . . . . .

    Understanding ModelingUnderstanding Modeling

    RGB format550 Kb

    JPG format25 Kb

    Data Compression rarely Data Compression rarely leads to understandingleads to understanding

    Complexity reduction (e.g., Complexity reduction (e.g., modeling) leads to modeling) leads to interpretationinterpretation

  • Chemical system Biological system

    Commercial candidates(pharmaceuticals, flavors, additives, etc.)

    Experimental knowledge

    Ki Metabolism Toxicity...pH Stability Soly pKa ...

    Modified from G. Cruciani

    StructureStructure--Property CorrelationsProperty Correlations

  • ++

    Modified from G. Cruciani

    3D3D--DescriptorsDescriptors

  • ++

    Modified from G. Cruciani

    3D3D--DescriptorsDescriptors

  • Etot = Eel + ELJ + Ehb + Eent

    Modified from G. Cruciani

    3D3D--DescriptorsDescriptors

  • Modified from G. Cruciani

    3D3D--DescriptorsDescriptors

  • Modified from G. Cruciani

    3D3D--DescriptorsDescriptors

  • StructureStructure--Based Drug DesignBased Drug Design

    M von Itzstein et al., Nature, 363:418 - 423, 1993

  • O=C1N(C)C(=O)N(C)C(=C12)N=CN2C

    CN1C(=O)N(C)C(=O)c(c12)n(C)cn2

    Cover Art for Chemoinformatics in Drug Discovery, Wiley VCH 2005

    The Many Facesof Caffeine

  • Combinatorial & Medicinal Chemist