Drug-like properties (1) Flashcards
Week 22 - 21st Jan 2025
What are drug-like properties?
Drug-like properties confer good ADME/Tox (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics to compounds, essential for creating balanced clinical candidates.
List some key structural properties
- Hydrogen bonding
- Lipophilicity
- Molecular weight
- pKa (Acidity/Basicity)
- Polar surface area (PSA)
- Shape and reactivity
List some key physicochemical properties
- Solubility
- Permeability
- Chemical stability
List some key biochemical properties
- Metabolism (Phases I and II)
- Protein and tissue binding
- Transport (uptake and efflux)
What properties does a good candidate have?
- Stable: Resistant to environmental conditions.
- Selective: Specific to the intended biological target.
- Soluble: Sufficiently dissolves for absorption.
- Safe: Minimal toxicity.
MK-0731
- Kinase inhibitor developed against a mitotic human kinase
- Entered phase I clinical trials but development stopped after phase I
- The compound was so insoluble that it had to be administered via IV for 24 hours
Barriers to Drug Exposure in Living Systems
Drug concentration at the therapeutic target depends on the combined performance at all barriers in the body.
Key barriers to drug exposure
- Membranes
- Metabolic enzymes
- Solution pH
- Efflux transporters
- Binding proteins
Mouth & Stomach barriers
Solubility is pH-dependent, chemical instability due to hydrolysing enzymes.
GI tract barriers
- Dynamic pH affects solubility, bile solubilises lipids to enhance absorption, and pancreatic enzymes may hydrolyse drugs.
- Dynamic environment: acidic pH at the stomach, acid-neutral pH in small intestine, basic in the colon
- Higher absorption of drugs in the small intestine due to wide pH and particularly high surface area
Veber rules
Oral bioavailability in rats improves when:
- ≤ 10 rotatable bonds
- PSA ≤ 140 Ų
- ≤ 12 total hydrogen bonds
Polar surface area (PSA)
- The polar surface area of a molecule is defined as the surface sum over all polar atoms, primarily oxygen and nitrogen, also including their attached hydrogens.
- Molecules with a polar surface area of greater 140 Ų tend to be poor at permeating cell membranes. For molecules to penetrate the BBB, a PSA less than 60 Ų is usually needed.
Lipophilicity
- Lipophilicity refers to the ability of a chemical compound to dissolve in fats, oils, lipids and non-polar solvents such as for example octanol.
- Determines ADME/Tox properties
- Can be estimated using log P or log D
- Optimal log P range is 0-3
pKa
- Reflects a compound’s ionizability.
- Ionized molecules are more soluble but less permeable.
- Acidic drugs ionize more in basic environments (e.g., small intestine), while basic drugs ionize more in acidic environments (e.g., stomach).
- Around 75% drugs are basic, 20% are acidic, and 5% are non-ionisable
Solubility ranges
- Low solubility: < 10 μg/ml (< 1 μM)
- Moderate solubility: 10–60 μg/ml (1 μM < x < 100 μM)
- High solubility: > 60 μg/ml (>100 μM)
Strategies to improve solubility
- Add ionisable group
- Reduce log P
- Add hydrogen bonding
- Add polar group
- Reduce molecular weight
- Construct a prodrug
Permeability
- Measures a molecule’s ability to cross membranes.
- Low permeability drugs often have poor bioavailability.
Strategies to improve permeability
Add lipophilicity, reduce polarity, and use non-ionizable groups.
Doxorubicin
- Topoisomerase 2 inhibitor, intercalates into DNA, generates reactive oxygen species
- MW: 543, H-bond donors: 6, H-bond acceptors: 12, C Log P: -1.7.
- Outcome: Low bioavailability (5%) - as expected from a drug that shows so many violations of Lipinski’s rules
Taxol
- Complicated molecule, microtubule-stabilising drug
- MW: 852, H-bond donors: 4, H-bond acceptors: 13, Log P: 4.5.
- Outcome: Low bioavailability, IV dosing required.
- Very successful cancer drug
