Principle of Drug Design

Question 1

What is the primary goal of drug (lead) optimization?

Answer 1

• To enhance a drug’s interaction with its target
  binding site.
• Increase activity and selectivity.
• Minimize side effects.

Question 2

What role does structure-based drug design play in lead optimisation?

Answer 2

• Relies on X-ray crystallography and computer-based
  molecular modelling.
• Allows researchers to visualize how lead
  compounds and their analogues bind to a target.
• Guides the rational design or modification of compounds for better fit and function.

Question 3

Why is the compound with the strongest binding to the target not always the best medicine?

Answer 3

• Pharmacokinetics (absorption, distribution, metabolism, excretion) and toxicity must be considered.
• A compound’s overall ADME profile and safety might not align with clinical use, despite strong binding affinity.
• Optimal drugs balance binding interactions with other essential properties to ensure efficacy in patients.

Question 3

T/F: The best binder always the best drug?

Answer 3

False - drug efficacy depends on more than just target affinity, ADME properties are essential. The drug must also be safe and well tolerated clinically.

Question 4

What are the three principal phases of drug action, and what do they determine?

Answer 4

1. Pharmaceutical Phase – Determines how much of the drug becomes available for absorption (e.g., disintegration, dissolution).
2. Pharmacokinetic Phase – Determines how much of the drug reaches the site of action (via absorption, distribution, metabolism, excretion).
3. Pharmacodynamic Phase – Determines how the drug interacts with tissues/receptors to produce a therapeutic effect.

Question 5

What is the significance of the pharmaceutical phase?

Answer 5

• Involves formulation and dosage form (e.g., tablet, capsule).
• Process of disintegration (breaking apart) and dissolution (dissolving).
• Directly impacts how much drug is available to be absorbed into the bloodstream.

Question 6

What is the main focus of the pharmacokinetic phase (ADME)?

Answer 6

Absorption: Getting from the site of administration into circulation.

Distribution: Traveling through blood to tissues and target sites.

Metabolism: Conversion into active/inactive forms (often in the liver).

Excretion: Removal from the body (commonly via kidneys or bile).

Overall, it determines how much drug ultimately makes it to the target and for how long.

Question 7

How does the pharmacodynamic phase differ from the other two phases?

Answer 7

Focuses on the drug’s effect on the body, i.e., the mechanism of action at the receptor or target site.

Encompasses therapeutic effects and side effects based on how strongly and selectively the drug binds to its biological targets.

Question 8

What is the goal of lead optimization in drug design?

Answer 8

Improve activity and selectivity at the target.

Enhance pharmacokinetic characteristics (e.g., better absorption, stable metabolism).

Minimize side effects and toxicity.

Ensure the final compound performs well in real-world biological systems (not just in binding assays).

Question 9

What strategies are commonly used to optimize a lead compound?

Answer 9

Variation of substituents on the core structure.

Extension of the molecule (adding new functional groups).

Isosteric or bioisosteric replacement (swapping chemical groups with similar properties).

Simplification of overly complex structures (removing non-essential parts).

Question 10

What are the major enteral routes of drug administration?

Answer 10

• Oral (by mouth)
• Rectal (suppository) or vaginal (pessary)
• Buccal (between gum and cheek) and sublingual (under the tongue)

Question 11

What are examples of parenteral and other administration routes?

Answer 11

Parenteral: Intravenous (IV), intramuscular (IM), subcutaneous (SC)
Other: Ocular (eye drops), nasal/pulmonary (inhaled), transdermal (topical creams, patches)

Question 12

What are the three main categories of dosage forms?

Answer 12

Liquid formulations: solutions, suspensions, emulsions

Semisolid formulations: creams, ointments, gels

Solid formulations: tablets, capsules

All require suitable excipients to ensure stability and bioavailability.

Question 13

What is the main objective of the pharmacokinetic phase?

Answer 13

Optimizing drug availability at the target site.
Involves absorption, distribution, metabolism, excretion (ADME) to ensure sufficient active drug reaches its site of action.

Question 14

What are the key “partition steps” a drug undergoes to reach its receptor?

Answer 14

Leaving aqueous extracellular fluid
Crossing the lipid membrane
Re-entering an aqueous environment before binding to its target

Question 15

What factors influence a drug’s ability to reach its target tissue?

Answer 15

Hydrophilic/hydrophobic balance
Ionization state
Molecular size
Chemical & metabolic stability

These properties affect how easily a drug crosses membranes and survives in the body.

Question 16

What are potential problems related to drug metabolism?

Answer 16

Loss of activity: Metabolites might be inactive.

Increased toxicity: Some metabolites can be more harmful.

Variable enzyme activity: Differences in cytochrome P450 and other enzymes among individuals affect drug response.

Question 17

Why is the drug–receptor interaction critical in pharmacodynamics?

Answer 17

Determines efficacy (how well it activates or blocks a receptor) and selectivity (specificity for the target).

Informs the pharmacophore—the essential features needed for activity.

Guides Structure-Activity Relationship (SAR) studies to improve therapeutic profiles.

Question 18

What is a pharmacophore, and why is it important?

Answer 18

A pharmacophore is the 3D arrangement of molecular features necessary for a drug’s biological activity.

It focuses optimization efforts, ensuring modifications retain or enhance the crucial interactions with the target receptor.

Question 19

What is the primary purpose of Lipinski’s Rule of Five in drug design?

Answer 19

It’s a simple “rule of thumb” to gauge whether a molecule has properties compatible with reasonable oral absorption.

Proposed by Chris Lipinski at Pfizer, derived from surveying marketed drugs.

Question 20

What are the key criteria in Lipinski’s Rule of Five?

Answer 20

No more than 5 hydrogen bond donors (sum of OH and NH groups).

A molecular weight (MW) below 500 Da.

A log P (lipophilicity measure) below 5.

No more than 10 hydrogen bond acceptors (sum of N and O atoms).

Question 21

Do Lipinski’s rules ensure a compound will be pharmacologically active?

Answer 21

No. They only suggest a molecule is likely to be orally bioavailable.

Activity still depends on target specificity, pharmacodynamics, and other biochemical factors.

Question 22

How do absorption, distribution, and metabolism impact a drug’s effect at its receptor?

Answer 22

They determine the amount of drug that actually reaches and remains at the target site.

Poor ADME properties can render even a potent drug ineffective or toxic in vivo.

Question 23

Why is lipophilicity and ionization important for passive membrane crossing?

Answer 23

Lipophilic and unionized compounds cross lipid membranes more easily.

Ionized or highly polar drugs may struggle to permeate cell membranes, affecting their bioavailability.

Question 24

Why should drugs generally have the lowest possible log P?

Answer 24

Minimizes nonspecific binding and toxicity. Increases ease of formulation and bioavailability. Reduces issues with accumulation in lipid-rich tissues.

Question 25

Why is stereospecificity critical in rational drug design?

Answer 25

Biological targets (enzymes, receptors) may prefer one enantiomer over another. Different stereoisomers can exhibit varying levels of efficacy, affinity, or toxicity. Optimizing stereochemistry is essential to develop safer, more effective drugs.

Question 26

What is a typical model for rational drug design?

Answer 26

Find a lead compound. Study Structure-Activity Relationships (SAR) and modify the structure. Identify the pharmacophore (crucial binding features). Generate new analogues. Evaluate and refine to achieve optimum therapy (efficacy, safety, stability).

Question 27

What is a “drug target” (sometimes called a drug receptor)?

Answer 27

A structure or macromolecule associated with a disease that a drug binds to. Can be on the cell surface or inside the cell (e.g., proteins, nucleic acids).

Question 28

Which types of macromolecules can act as drug targets?

Answer 28

Enzymes Receptors Carrier proteins Structural proteins Nucleic acids Lipids Carbohydrates

Question 29

What is meant by an “agonist” at a receptor?

Answer 29

A drug that mimics the natural ligand (e.g., neurotransmitter or hormone) Activates the receptor, producing a biological response.

Question 30

How does an “antagonist” work at a receptor?

Answer 30

It binds to the receptor but doesn’t activate it. Blocks the binding of the natural messenger or prevents receptor activation. May bind at the active site or an allosteric site, causing structural changes that affect signalling.

Question 31

What are possible outcomes of binding an allosteric site on a receptor?

Answer 31

Inhibition: Changing the receptor conformation to reduce natural messenger binding. Potentiation: Enhancing receptor affinity for the natural ligand.

Question 32

What are the main categories of enzyme inhibitors?

Answer 32

Competitive inhibitors: Compete with substrate for the active site. Non-competitive inhibitors: Bind to an allosteric site, changing enzyme conformation. Reversible inhibitors: Bind temporarily and can dissociate. Irreversible inhibitors: Form stable covalent bonds, permanently inactivating the enzyme. Transition state mimics: Resemble high-energy intermediate, binding tightly to the active site.

Question 33

Name three families of membrane-bound receptors and their general roles.

Answer 33

G-protein coupled receptors (GPCRs): Activate intracellular G-proteins to trigger signalling cascades. Ligand-gated ion channels (ionotropic receptors): Open an ion channel upon ligand binding for fast cellular responses. Kinase-linked receptors: Typically stimulate phosphorylation events within the cell to regulate gene expression and other processes.

Question 34

What are some non-receptor, non-enzyme targets for drugs?

Answer 34

Structural proteins (e.g., microtubules targeted by vincristine) Nucleic acids (e.g., intercalators, alkylating agents, antisense strategies) Lipids (e.g., anesthetics that alter membrane fluidity) Carbohydrates on the cell surface (e.g., drugs affecting cell recognition or adhesion)

Question 35

Which mechanisms of action are most common among first-in-class small-molecule NMEs?

Answer 35

They often work by inhibiting enzymes or modulating receptors. Novel mechanisms can lead to entirely new therapeutic classes.

Question 36

What basic requirements must a drug meet for successful receptor binding?

Answer 36

Correct binding groups (functional groups that can interact with the target). Proper spatial arrangement (groups positioned correctly for binding). Appropriate molecular size to fit the binding site. Must form the right types of interactions (e.g., hydrogen bonds, hydrophobic interactions) based on its functional groups and the receptor’s binding site.

Question 37

Which factors primarily influence a drug’s binding and overall action?

Answer 37

Molecular structure (shape and functional groups). Isomerism (the arrangement of atoms in space). Functional groups (which govern binding interactions). Rigidity or flexibility (more rigid structures may bind in a specific conformation, while flexible ones adapt to multiple conformations).

Question 38

What are the two main approaches to drug design?

Answer 38

Receptor-based (target-based): Begins with a known target structure (e.g., via X-ray crystallography). Ligand-based: Relies on known active compounds (ligands) and their structure-activity relationships (SAR) to guide optimization.

Question 39

What is a pharmacophore, and why is it important?

Answer 39

An abstract description of molecular features necessary for recognition by a biological macromolecule. Summarizes the key binding groups (e.g., H-bond acceptors, hydrophobic regions, aromatic rings) required for biological activity.

Question 40

Which functional groups are typically highlighted in a pharmacophore model?

Answer 40

Hydrophobic regions (often depicted in one color). Aromatic rings. H-bond acceptors and donors. Any other group known to be essential for receptor binding.

Question 41

What are the two major aspects of drug optimization?

Answer 41

Optimizing access to the target (Pharmacokinetics) – Ensuring the drug has suitable ADME properties. Optimizing target interactions (Pharmacodynamics) – Enhancing binding affinity, specificity, and functional activity at the receptor.

Question 42

Why might modifying the structure of a lead compound be necessary?

Answer 42

To improve binding interactions and selectivity. To optimize pharmacokinetic properties (absorption, distribution, metabolism, excretion). To reduce toxicity or side effects.

Question 43

Can you give an example of a critical functional group for analgesic activity?

Answer 43

A free phenolic OH group is often crucial for certain analgesics (e.g., in opioid structures), highlighting the importance of specific functional groups in maintaining activity.

Question 44

What are the essential binding groups in the analgesic’s pharmacophore, and how do they interact with the receptor?

Answer 44

Phenolic –OH: Forms hydrogen bonds. Aromatic ring: Engages in van der Waals interactions. N-methyl group: Participates in ionic bonding. These groups are arranged in a T-shaped conformation, crucial for receptor recognition.

Question 45

Why does the mirror-image (enantiomer) of this analgesic lack activity?

Answer 45

The reversed stereochemistry prevents correct alignment of key binding groups with the receptor’s binding sites. Only one enantiomer fits the required pharmacophore arrangement, so the mirror image cannot fully engage the receptor.

Question 46

What is drug extension, and why is it used in lead optimization?

Answer 46

Drug extension adds extra binding groups to the original structure. This strategy probes for additional binding sites on the receptor surface. The goal is to enhance drug–receptor interactions and potentially improve potency or selectivity.

Question 47

How does changing the length or size of substituents help in drug optimization?

Answer 47

Filling additional hydrophobic pockets within the binding site can enhance potency. Adjusting substituents can introduce selectivity for one target over another. Increases or decreases in substituent size/length can refine the fit between drug and receptor.

Question 48

What is “extension” in drug optimization, and why is it used?

Answer 48

Involves adding extra functional groups to the lead structure. Explores additional binding regions in the target site. Aims to improve drug–target interactions and potentially boost specificity or potency.

Question 49

How does modifying the chain connecting two binding groups help optimize a drug?

Answer 49

Adjusting chain length maximizes each group’s interaction with its binding region. Correct length/angle can enhance affinity and selectivity. Too long or too short a chain may reduce overall binding strength.

Question 50

What are the benefits of modifying or adding rings in a lead compound’s structure?

Answer 50

Novel scaffolds can lead to new drug classes with improved properties. Ring fusion can enhance receptor binding or increase specificity to avoid off-target effects. Changing ring size or substituents can optimize hydrophobic or electronic interactions.

Question 51

What role do isosteres play in drug optimization?

Answer 51

Isosteric replacement swaps functional groups with ones having similar size and electronic properties. Helps retain or enhance activity while potentially improving ADME or reducing toxicity. Often used to overcome metabolic liabilities or patent restrictions.

Question 52

Why might a drug designer simplify a lead compound, and what are the risks?

Answer 52

Removing non-essential groups lowers complexity and cost of synthesis. Can eliminate unnecessary stereocenters or structural elements not needed for activity. Risk: Oversimplification can lead to excessive molecular flexibility, decreasing activity and selectivity.

Question 53

What are conformational blockers, and why introduce them into a lead structure?

Answer 53

Bulky substituents or ring constraints added to limit conformations. Encourages the molecule to adopt the active binding conformation. Reduces entropy cost upon binding, potentially improving potency and selectivity.