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.