Discovery of Lead Compounds- Molecular Properties Flashcards
Why is it important to know molecular properties of small molecules?
Knowing molecular properties is essential to optimize small molecules for desirable drug-like characteristics, such as solubility, stability, and permeability, which influence the compound’s effectiveness and safety in the body.
What are the structural properties relevant to drug-likeness?
Structural properties include hydrogen bonding, lipophilicity, molecular weight, pKa, polar surface area, shape (conformation), and reactivity. These properties impact how well a drug interacts with biological systems.
What physicochemical properties are crucial for drug design?
Key physicochemical properties are solubility, permeability, and chemical stability. These properties affect how a drug is absorbed, distributed, and retained in the body.
Describe the biochemical properties that influence a drug’s behavior.
Biochemical properties include metabolism (phases I and II), protein and tissue binding, and transport mechanisms (uptake and efflux), which collectively impact how drugs are processed in the body.
Define pharmacokinetics (PK) and explain its components.
Pharmacokinetics (PK) studies how a drug is absorbed, distributed, metabolized, and excreted. Key PK components include clearance, half-life, bioavailability, drug-drug interaction potential, and toxicity (LD50).
What is Lipinski’s Rule of Five and its relevance?
Lipinski’s Rule of Five states that orally active drugs should have ≤5 hydrogen bond donors, ≤10 hydrogen bond acceptors, a molecular weight < 500 Da, and a ClogP < 5. It is a guideline to predict the drug-likeness of a compound, though some exceptions exist.
What are lead-likeness and drug-likeness?
Lead-likeness refers to a compound’s structural and physicochemical similarity to a “lead” compound. Drug-likeness describes a compound’s similarity to known drugs, indicating potential for successful development.
How does pH affect the molecular properties of drugs like norfloxacin?
Changes in pH can alter a drug’s charge, conformation, and lipophilicity, impacting its solubility and ability to cross cell membranes. For example, norfloxacin has different charges and lipophilic properties at different pH levels.
What is membrane permeability and why is it important in drug design?
Membrane permeability is the ability of a drug to cross cellular membranes. It is crucial for drugs targeting intracellular sites, as permeable drugs are more likely to reach their targets effectively.
Describe the blood-brain barrier and its function.
The blood-brain barrier (BBB) is a selective barrier that restricts passage of substances from the blood into the brain. It protects the brain but also limits drug entry, impacting drug design for CNS-active compounds.
What role do efflux transporters like P-glycoprotein (P-gp) play?
Efflux transporters, such as P-gp, pump foreign substances out of cells, often contributing to drug resistance in cancer by removing therapeutic agents from tumor cells. They are expressed in organs like the brain, gut, liver, and kidneys.
What are the molecular properties that enhance CNS drug permeability?
CNS drugs typically have higher lipophilicity, fewer hydrogen bond donors, lower polar surface area, reduced flexibility, and fewer positive charges compared to non-CNS drugs, aiding in BBB penetration.
Explain the concept of multi-parameter optimization (MPO) in drug design.
MPO balances a drug’s properties (e.g., pharmacokinetics, pharmacodynamics, safety) to optimize efficacy and reduce side effects, particularly important for CNS drug development.
What is a substrate and how does it differ from an inhibitor in drug transport?
A substrate is a molecule that a transporter protein moves across a membrane, while an inhibitor blocks the transporter, potentially enhancing or reducing drug effects. For example, P-gp inhibitors can increase drug retention in cells.
Describe a chemical approach using lipophilic analogues in drug design.
Lipophilic analogues enhance membrane permeability by increasing lipophilicity, but excessive lipophilicity can reduce tissue selectivity and cause poor distribution.
