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Biostat lecture 2

Medical Informatics and Biostatistics

  • Key concepts in medicine: data, informatics, knowledge
  • Importance of coding in drug structure with molecular editors.
Molecular Targets
  • Receptors: Act as molecular targets.
  • Molecular Descriptors: Key terms include lipophilicity, which is crucial for drug design.

Computer-Assisted Molecular Design (CAMD)

  • Incorporates QSAR modeling.
  • Artificial Intelligence (AI): Essential in medicine, especially neural networks (NN).
  • Understanding basics of biostatistics, data preprocessing, data modeling techniques, visualization, and grouping is essential.

Overview of In-Silico Medicine

  • Importance of computational methods for drug design and research in biostatistics.

Protein Chemistry: Historical Perspective

  • Early Discoveries:
    • 1816: F. Magendi identifies proteins as dietary essentials.
    • 1839: G.J. Mulder introduces the term 'protein'.
    • Key contributions from W. Kuhne, F. Hoffmeister, and A. Kossel in identifying amino acids as building blocks of proteins.
    • 1953: Fredrick Sanger determines insulin’s structure, advancing protein sequencing.

Protein Structure and Functions

  • Common Features:
    • All proteins consist of amino acids linked by peptide bonds.
    • Classification based on the number of amino acids (dipeptide, tripeptide, oligopeptide, polypeptide).
  • Functions:
    • Structural (e.g., keratin), hormonal (e.g., insulin), catalytic (e.g., enzymes).

Amino Acids

  • Basic Structure: Contain an amino group (-NH2) and a carboxyl group (-CO2H).
  • 20 natural amino acids form the building blocks of proteins.
  • Can be classified as endogenous or exogenous based on their synthesis in the body.

Peptide Bonds

  • Formed between the α-carboxyl group of one amino acid and the α-amino group of another, releasing one water molecule (dehydration).
  • Short chains lead to dipeptides and tripeptides, categorized as polypeptides when exceeding 100 amino acids.

Structural Levels of Proteins

  • Primary Structure: Sequence of amino acids.
  • Secondary Structure: Includes alpha helices and beta sheets formed through hydrogen bonds between peptide bonds.
Tertiary Structure
  • Refers to the overall 3D shape due to side-chain interactions and the stabilization role of Van der Waals forces.
Quaternary Structure
  • Arrangement of multiple polypeptide chains (subunits) to form a functional protein.
  • Stabilizing interactions include different bonding types and structural arrangements.

Protein Classification by Function

  • Enzymes (e.g., pepsin), hormones (e.g., insulin), transport proteins (e.g., hemoglobin), structural (e.g., collagen), and protective proteins (e.g., antibodies).

Molecular Descriptors in Drug Development

  • Descriptor vs. Property:
    • Descriptors: Calculated values based on molecular structure.
    • Properties: Measured experimentally based on the behavior of drug molecules.

Understanding Lipophilicity

  • A vital physicochemical property relevant to pharmacokinetics and drug efficacy.
  • Lipophilicity ($ ext{log P}$): Measures drug solubility in fat vs. water, affecting drug absorption, distribution, metabolism, and excretion (ADMET).
  • Experimental Measurement: Techniques include shake-flask, TLC, and HPLC.

Ionization in Drug Chemistry

  • Approximately 85% of drugs have ionizable functionalities.
  • Ionization influences drug solubility and permeability across biological membranes.

Lipinski's Rule of Five

  • A guideline for designing drug-like compounds based on molecular characteristics (e.g., molecular weight, logP).
  • Violation of two or more criteria may indicate a molecule's potential to be a successful drug.

Congreve's Rule of Three and Simplified Drug Design

  • Parameters for lead compounds: MW ≤ 300, logP ≤ 3, NRB ≤ 3.
  • Emphasis on reduced complexity in drug design to improve success rates in compound identification.