Drug Discovery Process Quiz
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Which of the following is NOT a direct step in the drug discovery process as described in the provided content?

  • Activity model generation
  • Clinical studies
  • Lead identification
  • Searching for natural products (correct)

    • What is the primary purpose of 'structural and physicochemical filters' during the drug discovery process?

  • To identify the interaction place of a drug with a target
  • To optimize the activity profile of a lead compound
  • To assess the metabolic and toxic aspects of a drug
  • To evaluate the drug likeness of a ligand (correct)

    • According to the content, what is a key aspect considered during the 'docking' process?

  • The geometry between the ligand and its receptor (correct)
  • The ligand's similarity to other known compounds
  • The ADMET properties of the compound
  • The chemical stability of the compound

    • Which activity is NOT part of the post-processing steps after docking?

    <p>Similarity searching</p> Signup and view all the answers

    What is the main objective of 'SAR' in the context of drug discovery, based on the content?

    <p>To improve lead compounds through pharmacophore identification</p> Signup and view all the answers

    What does 'ADMET' refer to in the post-processing stage of drug discovery?

    <p>Aspects of absorption, distribution, metabolism, excretion, and toxicity</p> Signup and view all the answers

    Which of the following is a challenge associated with virtual drug design as described in the content?

    <p>Storing and searching chemical structures in a database</p> Signup and view all the answers

    Based on the text, what does a 'pharmacophore identification' help to determine?

    <p>The specific regions of a molecule responsible for its biological activity</p> Signup and view all the answers

    What is the primary goal when determining sample size?

    <p>To balance cost with the reliability of the results.</p> Signup and view all the answers

    Which of these MUST be true for a sample to be considered representative?

    <p>The sample is a miniature of the population retaining all its essential properties.</p> Signup and view all the answers

    What does sample randomness primarily ensure?

    <p>That every element of the population has an equal likelihood of inclusion in the sample.</p> Signup and view all the answers

    In statistical analysis, what is the term for values computed for the population?

    <p>Parameters</p> Signup and view all the answers

    Mathematical statistics is primarily divided into which two branches?

    <p>Estimation theory and statistical hypothesis verification</p> Signup and view all the answers

    Which of the following best describes the purpose of analysis of variance?

    <p>To establish whether deviations in experimental data are random or systematic.</p> Signup and view all the answers

    When categorizing sample sizes, what range defines a 'large sample'?

    <p>n &gt;= 30</p> Signup and view all the answers

    What does 'a statistical unit' refer to?

    <p>An individual element of the statistical population.</p> Signup and view all the answers

    In a Winner Takes All (WTA) neural network, what is the key characteristic regarding neuron activation?

    <p>Only one neuron with the strongest activation is excited.</p> Signup and view all the answers

    What is the distinguishing feature of a Winner Takes Most (WTM) network compared to a WTA network?

    <p>In WTM, neighboring neurons to the winning neuron also have their weights adjusted.</p> Signup and view all the answers

    What is the primary purpose of using a neighborhood function in a WTM network?

    <p>To determine how much to correct the weights of neurons neighboring the winning neuron.</p> Signup and view all the answers

    In the context of QSAR, what molecular property is often projected onto a 2D topographic map using CoMSA?

    <p>Electrostatic potential.</p> Signup and view all the answers

    What kind of data is entered into the Kohonen network when creating a CoMSA representation, regarding the molecule's surface?

    <p>Coordinates (x, y, z) of selected points on the van der Waals surface.</p> Signup and view all the answers

    What is done with the electrostatic potential values after mapping them to neurons in the CoMSA method?

    <p>They are scaled and averaged and assigned a color to make a 2D map.</p> Signup and view all the answers

    What is the purpose of superimposing 3D structures in the CoMSA method?

    <p>To align all compounds with a chosen reference compound for comparison.</p> Signup and view all the answers

    In the context of 3D-QSAR, how is the reverse image of a receptor characterized?

    <p>By a Kohonen reference map of the most active molecule.</p> Signup and view all the answers

    What is the primary purpose of the centering operation described?

    <p>To shift the data so that it is zero centered.</p> Signup and view all the answers

    What effect does the centering operation have on the distribution of samples in m-dimensional space?

    <p>It does not affect the distribution's overall shape, just shifts it.</p> Signup and view all the answers

    In the standardization formula, what does std(x_j) represent?

    <p>The standard deviation of the j-th column.</p> Signup and view all the answers

    What is the key outcome of standardizing the data?

    <p>Each variable contributes equally to the total variance.</p> Signup and view all the answers

    Given a dataset where the mean of a column’s values is $5$, how are the values changed during a centering operation?

    <p>Each value has $5$ subtracted from it.</p> Signup and view all the answers

    Before standardization, if two columns in a dataset have different standard deviations, what issue would this cause in data analysis?

    <p>It can give columns with larger standard deviations more influence on results.</p> Signup and view all the answers

    If a dataset is centered, but not standardized, what can be said about the contribution of its variables to the total variance?

    <p>Variables' contribution remains proportional to their standard deviation.</p> Signup and view all the answers

    Which of the following is NOT a typical use of descriptive statistics?

    <p>To make predictions about future data.</p> Signup and view all the answers

    Which of the following best describes the role of hypothesis testing?

    <p>To provide an objective framework for making decisions using probabilistic methods.</p> Signup and view all the answers

    In hypothesis testing, a one-sample problem involves making inferences about:

    <p>A single distribution.</p> Signup and view all the answers

    When conducting a hypothesis test, the hypotheses considered are formulated as:

    <p>Null and alternative hypotheses.</p> Signup and view all the answers

    Which statistical test is appropriate for comparing the means of two independent groups?

    <p>Student's t-test for independent groups.</p> Signup and view all the answers

    What needs consideration when using the Student's t-test?

    <p>The standard deviations of both groups should be similar.</p> Signup and view all the answers

    If there are more than two groups being compared, which type of test should be used?

    <p>Analysis of variance (ANOVA).</p> Signup and view all the answers

    In the given example, after calculating the t-statistic as 2.6789 and finding the critical value of t from the table as 2.16, what is the conclusion of the hypothesis test, if the significance level ($\alpha$) is equal to 0.05?

    <p>The mean in group A differs significantly from the mean in group B with a probability of p.</p> Signup and view all the answers

    In calculating the standard error of the difference between two means, the degrees of freedom are calculated as:

    <p>The sum of the degrees of freedom of each sample.</p> Signup and view all the answers

    In graph theory, what do 'V' and 'E' typically represent?

    <p>Vertexes and Edges</p> Signup and view all the answers

    What is a neighboring matrix (adjacency matrix) used for in the context of molecular graphs?

    <p>To encode the connectivity between atoms in a molecule.</p> Signup and view all the answers

    Which of the following is NOT a typical component of a connection table (CT) used in chemistry?

    <p>Spatial coordinates of each atom in 3D space.</p> Signup and view all the answers

    What is the purpose of a molecular editor in the context of computational chemistry?

    <p>To visually display and manipulate molecule structures and generate connection tables.</p> Signup and view all the answers

    What does the acronym SMILES stand for?

    <p>Simplified Molecular Input Line Entry System</p> Signup and view all the answers

    Which of the following SMILES notations represents a double bond?

    <p>=</p> Signup and view all the answers

    What does 'CANGEN' refer to, within the context of SMILES notation?

    <p>An acronym for 'Canonicalization and Generation'.</p> Signup and view all the answers

    In SMILES notation, what do square brackets ( [] ) generally indicate?

    <p>Charged or non-standard atoms.</p> Signup and view all the answers

    Study Notes

    Contact Information

    In-silico Medicine Outline

    • Data, informatics, knowledge in medicine
    • Coding of drug structure – molecular editors
    • Receptors as molecular targets
    • Molecular descriptors – lipophilicity
    • Computer Assisted Molecular Design (CAMD) – QSAR modeling
    • Artificial intelligence in medicine (AI) – essentials of neural networks (NN)
    • Basics of biostatistics
    • Data preprocessing
    • Basic procedures of data modeling
    • Essential techniques of data visualization and data grouping

    Literature of Subject

    • Edited by Thomas Engel and Johann Gasteiger
    • Chemoinformatics: Basic Concepts and Methods
    • Textbook of Medical Statistics (for Medical Students, editors Xiuhua Guo and Fuzhong Xue)
    • Introduction to Medicinal Chemistry (seventh edition, by Graham L. Patrick)
    • Wold Wide Web database

    Computer Assisted Drug Design (CADD)

    • AIM – production of substances that act in the human body →rational drug production
    • Molecular production of properties → drug modeling

    Medicine

    • Medicine – the art of human treatment/healing
    • Pharmacy/Pharmacology/Medicinal Chemistry: The science of molecules and their transformations
    • Drug Molecule: A molecule with medicinal properties
    • Paracelsus XVI century quote – “All things are poison, and nothing is without poison, only the dose permits something not be poisonous.”

    History of Drug Discovery

    • 5100 years ago – China: Chiang Shan herbs (fever), Ma Huang (anti-cough drug)
    • 3 w.p.n.e.: Extract from poppy grain (pain-killers), scopolamine (truth serum), Belladona (atropine)
    • Inca nations: coca (energizing)
    • India: rezorcinol (high blood pressure)
    • 1633: Calancha monk – extract from quina tree (drug to malaria)
    • 1928: Alexander Fleming – penicillin (antibiotics, antybiotos)
    • “Sometimes you find what you are not looking for”
    • “The Nature produced penicilline, I have just discovered it”

    Accident = Serendipity - "lucky shot"

    • Engineer in the military health service
    • Study of biological discharge to kill bacteria
    • Lisozyme (1921) - first antibiotics
    • Penicillin (1928): fungus (Penicillium notatum) → Staphylococcus
    • 1941: Florey and Chain – experiment on mice (infected with streptococcus)
    • 1941: Albert Aleksander – patient 0 (experiment with thorn of rose) and patient survival despite death
    • Karl Folkers (Merk) – specification of Penicillin structure

    Medicinal Product

    • Directive 2001/83/EC of the European Parliament and the Council (November 6, 2001) → any substance or mixture of substances intended for diseases in humans or animals, and substance/mixture of substances used for diagnosis or restoring, correcting or modifying physiological functions

    Classification of Drug Molecules

    • Natural compounds - materials from plants and animals (e.g. vitamins, hormones, amino acids, antibiotics, alkaloids, glycosides)
    • Synthesis compounds - pure synthesis or synthesis from naturally occurring compounds (e.g. morphine, atropine, steroids, cocaine
    • Semi-synthesis compounds - compounds that cannot be purely synthesized or isolated from natural sources inexpensively thus using natural intermediates for desired product (e.g. semi-synthetic penicillins)

    Data Exploration

    • Graph of compounds published in CAS, rising exponentially since 1965
    • Graph relating number of new drugs & R&D spending exhibiting a negative trend correlating to log-scale graph exhibiting an exponential negative trend

    Why new drugs are so expensive?

    • Absorption
    • Distribution
    • Metabolism
    • Excretion
    • Toxicity
    • ADMET

    Drug Analysis

    • 2D → 3D molecular generators (CORINA, MOPAC, BABEL, SYBYL, MOE, etc.) → input data
    • Pre-processing/descriptor selection (scaling, centering, standardization)
    • Structure coding
    • Statistical methods
    • Artificial intelligence (neural networks)
    • Data analysis

    Chemoinformatics of Drugs

    • Molecule
    • Structure
    • Descriptors
    • Data Analysis
    • Database Exploration
    • Measures

    From data to Drugs

    • Chemoinformatics (pharmacophore, serendipity)
    • Bioinformatics (de novo)
    • Similarity searching
    • Molecular docking

    Two Directions of Drug Design

    • Ligand-based Drug Discovery (RI): ligand collection → maps of interactions → reverse image of target structure
    • CC&HTS → lead structure → optimization → clinical studies
    • Structure-based Drug Discovery (RD): searching for drugs of low molecular weight as complementary fulfillment of target molecule
    • Identification of target → preparation of target molecule → docking → assessment of bioactivity

    Two Directions of CAMD Study

    • Preparation of receptor and ligand
    • Structural and physicochemical filters
    • Drug likeness
    • Docking
    • Ligand-receptor geometry
    • Post processing
    • Scoring/Rescoring
    • Variable selection
    • Activity prediction
    • Model assessment
    • Pose evaluation
    • ADMET
    • Chemical stability

    Drug → from idea to implementation

    • Disease specification → Optimization of Lead
    • Determination of interaction place → Identifying pharmacophore
    • Selection of biological test → Identification of Lead

    • Metabolic and toxic studies → Clinical studies → Final Drug Confirmation

    Directions of future evolution in drug design and medicine

    Searching for synthetic analogues of natural products NP → Searching for leading structures of selected biological targets → Personalized Drug Design

    Virtual Drug Coding Problems

    • Storing molecular structure in a database
    • Searching structures in a database
    • Deriving structures from measured data
    • Predicting properties for a structure
    • Treating chemical reactions and synthesis planning

    Chemical presentation of drugs.

    • 3D model
    • Model 2D
    • Nomenclature (Chemical names)
    • Content (Chemical structures)
    • Information structure

    Racemic Mixtures Stereochemistry

    • Oral medication for cancers (e.g. multiple myeloma) and skin disorders
    • Human teratogen with life-threatening birth defects during pregnancy
    • Skeletal deformities (amelia, absence of legs/arms); phocomelia (limb malformation)
    • (R)-enantiomer → sedative effect and (S)-enantiomer → embryo-toxic and teratogenic effect.
    • Enantiomers can racemize to each other in vivo

    Linear notation in drug coding

    • Trivial name: Phenylalanine
    • IUPAC name: 2-amino-3-phenylpropanoic acid
    • WLN: VQYZ1R
    • ROSDAL: 10-2=30,2-4-5N,4-6-7=-12-7
    • Smiles: NC(Cc1ccccc1)C(O)=O
    • SLN: C[1]H:CH:CH:CH:CH:C(:@1)CH2CH(NH2)C(=O)OH

    Molecular surfaces in drug design

    • Van der Waals' surface
    • Connolly's surface

    Graph theory

    • L. Euler (1736) → Königsberg’s seven bridges problem
    • Molecular graphs G={V,E}
      • V = vertexes (atoms), E = edges (bonds)
    • Drug – undirected coherent graph

    Coding of Drug Constitution

    • Neighboring matrix/bonding matrix
    • Connection table CT

    Drug in MDL Molfile format

    • Compound information and properties, formatted as a text file for importing and using chemical compounds

    Molecular Editors

    • Molecule editor
    • Viewer
    • Connection table

    Survey of molecular editors

    • Various software tools (Chem3D, ChemDraw, ACD/ChemSketch, ISIS/Draw, etc.) for molecular structure drawing, analysis, and manipulation

    SMILES (Simplified Molecular Input Line Entry System)

    • Entering molecular structure using a set of rules;
    • Generating unique representations

    Statistical Metrics

    • Arithmetic mean
    • Geometric mean
    • Median
    • Standard deviation
    • Variance
    • Kurtosis
    • Skewness

    Basic parameters of statistical data

    • Variance and standard deviation

    Scaling, centering, standardization

    • Formulas for scaling, centering, and standardization of data

    Estimation in Statistics

    • Estimation of the mean of a distribution
    • Point estimation
    • Interval estimation (t distribution)

    Hypothesis Testing

    • One-sample t-test for the mean of normal distribution with unknown variance

    Two-Sample t Test for independent samples with equal variances

    • Test statistic formula

    Types of Statistics

    • Descriptive statistics: Continuous, discrete, proportions, central tendency, dispersion
    • Inferential statistics: Estimation, hypothesis testing, p-values, confidence intervals

    Planning/Design of the Study

    • Primary question
    • Sample size
    • Participant selection
    • Group assignment

    Biomedical research

    • Relationship between patient characteristics/treatments and a health condition
    • Establishing cause and effect

    Errors

    • Nonsampling error
    • Sampling error:
      • Error of measurement
      • Error of non-response
      • Error of misinterpretation
      • Error of calculation or arithmetical error
      • Error of sampling bias

    Statistical Community

    • One-dimensional versus Multidimensional
    • Static versus Dynamic
    • Relatively homogeneous versus Heterogeneous
    • Qualitative versus Quantitative

    Populations and Samples

    • Population
    • Sample
    • Representative sample
    • Random sample

    Regression and Correlation Methods

    • Relate a normally distributed output variable
    • Types of correlation: Linear positive, linear negative, non-linear
    • Pearson linear correlation coefficient

    ANOVA

    • Hypotheses for comparing three+ groups
    • ANOVA formula/calculation

    Telemedicine

    • Use of information and communication technologies to transfer medical data;
    • Types: Teleoperations, telemonitoring, teledagnosis, teleradiology, telecardiology;
    • Models: Direct, intermediate
    • Benefits, barriers, needed requirements

    Biomolecules

    • Primary sequence representation of biomolecules

    Molecular Descriptors

    • Representation of molecular properties into numbers
    • Descriptor dimensionality (1D, 2D, 3D)

    Lipophilicity

    • Importance in medicinal chemistry
    • Methods for measuring lipophilicity

    Pharmacophore concept

    • A collection of steric and electronic features
    • Drug-receptor interactions

    QSAR

    • Quantitative structure-activity relationship analysis to predict drug activity

    QSAR - Data Analysis Techniques

    • Approaches for analyzing data (artificial intelligence, neural networks, Hebb rule, Kohonen neural network)

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    Description

    Test your knowledge of the drug discovery process with this quiz. It covers various aspects such as drug design techniques, docking processes, and statistical analysis related to sample size. Understand key terminologies like SAR, ADMET, and pharmacophore identification through this engaging quiz.

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