Molecular Basis of Drug Action and Design Flashcards
(130 cards)
1
Q
What is the term for a substance that binds to a receptor and activates it?
A
Agonist
Agonists mimic the action of a naturally occurring substance.
2
Q
What is the term for a substance that binds to a receptor but does not activate it?
A
Antagonist
Antagonists block the action of agonists.
3
Q
What is the definition of pharmacophore?
A
Pharmacophore is the part of a molecule responsible for its biological activity
It includes the essential features required for interaction with a biological target.
4
Q
Fill in the blank: The _______ is the measure of the drug’s ability to produce a desired effect.
A
Efficacy
Efficacy refers to the maximum effect achievable by a drug.
5
Q
What does specificity refer to in pharmacology?
A
Specificity refers to the ability of a drug to bind to a particular receptor subtype
Higher specificity reduces side effects.
6
Q
What is selectivity in the context of drugs?
A
Selectivity is the preference of a drug to bind to one receptor over others
Selective drugs tend to have fewer side effects.
7
Q
Define potency in pharmacological terms.
A
Potency refers to the amount of drug needed to produce a given effect
A more potent drug requires a lower dose to achieve the same effect.
8
Q
What is affinity in pharmacology?
A
Affinity is the strength of the interaction between a drug and its receptor
Higher affinity means the drug binds more tightly to the receptor.
9
Q
Fill in the blank: The property of a drug to produce a greater response when combined with another substance is known as _______.
A
potentiation
Potentiation can enhance the effects of the primary drug.
10
Q
What is stereospecificity?
A
Stereospecificity refers to the preference of a receptor for one stereoisomer over another
This can significantly affect drug efficacy and safety.
11
Q
What is chirality in the context of drug molecules?
A
Chirality refers to the property of a molecule that makes it non-superimposable on its mirror image
Chiral drugs may have different effects based on their stereochemistry.
12
Q
What is the role of a receptor in pharmacology?
A
A receptor is a protein molecule that receives and responds to a ligand
Receptors play a key role in cellular communication and signaling.
13
Q
What are the types of drug action?
A
- Stimulation or depression of a functional activity
- Replacement of an essential compound
- Killing of foreign organisms, cancerous cells etc.
Essential compounds may include metabolites, regulators, or genes.
14
Q
What are the classifications of drugs based on their primary biological effects?
A
- Psychopharmaceutical agents acting on CNS
- Pharmacodynamic agents
- Chemotherapeutic agents
- Metabolic agents
CNS stands for Central Nervous System.
15
Q
What are the bases for the classification of drugs?
A
- Pharmacological effects
- Biochemical process they affect
- Chemical structure
- Molecular target
Each basis provides a different perspective on how drugs can be grouped.
16
Q
Fill in the blank: The action of drugs can involve the _______ of a functional activity.
A
stimulation or depression
17
Q
True or False: Chemotherapeutic agents are classified under drugs acting on the CNS.
A
False
Chemotherapeutic agents are a separate classification focused on killing foreign organisms or cancerous cells.
18
Q
What is one type of drug action that involves replacing essential compounds?
A
Replacement of an essential compound
This can include metabolites, regulators, or genes.
19
Q
Fill in the blank: Drugs can be classified according to their _______ effects.
A
pharmacological
20
Q
What type of agents act on the Central Nervous System?
A
Psychopharmaceutical agents
These agents are specifically designed to influence mental states and behaviors.
21
Q
What is the sequence of drug action leading to effects?
A
DRUG → BODY/CELL → ACTION(S) → EFFECT(S)
This sequence outlines the process from drug administration to the resulting physiological effects.
22
Q
What is meant by ‘mechanism of action’?
A
The underlying biochemical and pharmacological actions that lead to effects (responses)
This term describes how a drug produces its effects at the molecular or cellular level.
23
Q
Can a single action of a drug lead to multiple effects?
A
Yes
A single pharmacological action can result in various physiological responses.
24
Q
Can multiple actions of a drug result in a single effect?
A
Yes
Different actions can converge to produce the same therapeutic outcome.
25
What are primary effects of drugs?
Desired therapeutic effects
## Footnote
These are the main effects that a drug is intended to produce.
26
What are secondary effects of drugs?
Side effects
## Footnote
These are unintended effects that occur in addition to the primary therapeutic effects.
27
Provide an example of a drug with a secondary effect.
Antihistamines - drowsiness
## Footnote
Antihistamines are commonly used for allergy relief but can cause sedation as a side effect.
28
What is an example of a drug that causes loss of appetite as a secondary effect?
Amphetamine
## Footnote
Amphetamines are stimulants that may suppress appetite as a side effect.
29
What is the definition of a mechanism of drug action?
Involves interaction between the chemical and part(s) of the organism
## Footnote
The mechanism of action refers to how a drug produces its effects on the body.
30
What is an agonist?
Produces a response
## Footnote
Agonists activate receptors to elicit a biological response.
31
What is an antagonist?
Suppresses a normal response
## Footnote
Antagonists block or dampen the biological response by binding to receptors.
32
Why do we need new drugs? List at least three reasons.
* New ones with less side effects
* Drug resistance and tolerance
* To improve treatment of an existing disease
* To treat new diseases
* To give specific action on new targets for treating a disease
## Footnote
The need for new drugs is driven by various factors, including safety and efficacy.
33
What is drug discovery?
The process by which drugs are discovered and/or designed
## Footnote
This process includes various stages of research and development to identify new therapeutic agents.
34
What is the general strategy for drug discovery? List the main steps.
* Extract compound
* Check activity
* Determine molecular structure
* Synthesise analogues
* Deduce molecular features
* Synthesise new compounds to optimise activity
* Test
* Select lead
## Footnote
This strategy outlines the sequential steps involved in identifying and developing new drugs.
35
What is the first step in the processes of drug discovery and design?
Discovery of molecule as lead structure
## Footnote
The lead structure exhibits some level of the desired biological activity.
36
What is the purpose of optimisation in drug discovery?
To modify the lead structure to obtain the desired therapeutic agent
## Footnote
This process enhances the efficacy and safety of the potential drug.
37
Fill in the blank: A method of _____ is needed in drug discovery.
[assay]
## Footnote
Assays are essential for evaluating the biological activity of compounds.
38
What knowledge is crucial for effective therapy in drug discovery?
Knowledge of target for therapy
## Footnote
Understanding the biological target is key to developing effective drugs.
39
What was the nature of early drug discovery?
Serendipitous in nature
## Footnote
Example: The discovery of Penicillin
40
What was the first medicinal drug available derived from?
Willow leaves
## Footnote
Salicin was used during childbirth
41
What is the average time it takes from drug discovery to market approval?
12 - 15 years
42
What is the average development cost of a new drug?
More than £400 million
43
What are the key aspects tested in preclinical studies?
Safety testing
## Footnote
Includes testing for teratogenicity, carcinogenicity, and toxicity
44
What does LD50 measure?
The toxicity of a drug
45
What type of tests are conducted to assess toxicity before clinical trials?
In-vitro tests on cell cultures and in-vivo tests on mice
46
What are the two key proofs needed for a new drug?
Proof Of Principle and Proof Of Mechanism
47
What is the aim when administering a new drug to patients?
Achieve the desired effect without causing harmful side effects
48
What does PD stand for in drug evaluation?
Pharmacodynamics
49
What does PK stand for in drug evaluation?
Pharmacokinetics
50
Fill in the blank: The ideal preclinical model mimics _______.
human disease
51
What does pharmacokinetics describe?
Changes in plasma concentration as a consequence of ADME
52
What is the significance of the therapeutic index of a drug?
It establishes the safety and efficacy of the drug
53
What are in vitro preclinical studies?
Analysing in a petri dish
## Footnote
Fast, simple, efficient method for testing.
54
What is tested in yeast-based systems during in vitro studies?
Genotoxic effects
## Footnote
This helps identify potential DNA damage.
55
What are cell lines grown in vitro used for?
Proliferation and apoptosis testing
## Footnote
Includes assays like POP and POM.
56
What recent breakthrough has been made in preclinical studies?
Inducible pluripotent stem cells for phenotypic screening platforms
## Footnote
Utilizes tissue-specific cells of human origin.
57
What is the purpose of in vivo preclinical studies?
To assess compounds that show promise in cell-based assays in animal models.
58
Why are genetically engineered mice (GEM) used in studies?
To consider the complete organism with highly conserved genomes
## Footnote
99% of genes overlap with humans.
59
What is the requirement for preclinical evaluation of new drugs in Europe?
Testing in 2 species: one rodent and one non-rodent (dogs or monkeys).
60
What does NOAEL stand for?
Non-observed-adverse-effect dose level.
61
What is the recommended starting dose in humans for cytotoxic agents?
1/10th of the dose lethal to 10% of mice (LD10).
62
What is the purpose of toxicity testing?
To determine safe dose levels for future clinical trials.
63
True or False: Animal testing always predicts human toxicity accurately.
False.
## Footnote
Toxic properties observed in animals may differ from humans.
64
What percentage of promising drugs fail toxicity testing?
As low as 9%.
65
What are the key phases in the drug development cycle?
Pre-discovery, discovery, preclinical, early clinical, late clinical, marketing.
66
What does the drug development cycle start with?
Research-based concept study of disease mechanism.
67
What is assessed during late clinical phases?
Define target population, dose selection, and optimization.
68
Fill in the blank: The process from research concept to marketed product is _______.
Lengthy and costly.
69
What are the desired outcomes for a drug in preclinical trials?
Desired effect on animals, advantage over existing therapies, acceptable pharmacokinetics, few metabolites, no serious side effects.
70
Why must a drug have good selectivity for its target?
Ensures the drug primarily affects the intended biological target (e.g., specific enzyme or receptor).
Minimises off-target interactions that can lead to unwanted side effects.
Improves therapeutic efficacy and patient safety.
71
Why should a drug have a good level of activity for its target?
High potency means lower doses can be used.
Increases therapeutic benefit by strongly interacting with the intended target.
Reduces the likelihood of dose-related toxicity.
72
Why is it important that a drug has minimal side effects?
Enhances patient compliance and quality of life.
Reduces the risk of adverse reactions.
Increases the likelihood of regulatory approval.
73
Why should a drug be easy to synthesize?
Simplifies large-scale manufacturing.
Lowers production costs.
Helps achieve efficient and consistent quality control.
74
Why must a drug be chemically stable?
Ensures it retains efficacy over its shelf-life.
Prevents degradation products that could be toxic or less effective.
Maintains consistent dosing and therapeutic action.
75
What does “acceptable pharmacokinetics” mean in drug design?
The drug is absorbed, distributed, metabolized, and excreted in a way that maximizes efficacy.
Avoids rapid degradation or clearance that diminishes therapeutic effect.
Prevents accumulation in the body that could lead to toxicity.
76
Why must a drug be non-toxic?
Patient safety is paramount for clinical use.
Minimizes risk of severe adverse events.
Increases the probability of successful clinical trials and market approval.
77
What is the typical success rate, timeline, and cost for a drug to reach the market?
Success rate: Approximately 1 in 10,000 investigated medicines in the U.S. proceeds from the lab to FDA approval and pharmacy shelves.
Timeline: The entire process can take up to 15 years.
Cost: On average, around £1.7 billion per drug.
78
What is a New Molecular Entity (NME)?
An NME is a drug that has never been approved by the FDA or marketed in any form or derivative.
79
What are some common reasons a drug fails to move forward to approval?
Lack of efficacy: The drug simply does not work as intended.
Toxicity: Unacceptable safety profile or severe adverse effects.
Redundancy: Too similar to existing therapies, offering little clinical benefit.
Corporate or financial issues: Loss of interest, budget cuts, or strategic changes.
Limited market: Small patient population (e.g., rare diseases) may not justify development costs.
80
Why might a drug fail due to lack of efficacy?
It does not produce the intended therapeutic effect.
Clinical trials fail to show significant improvement over placebo or current standard treatments.
81
How can toxicity cause drug failure?
Unacceptable safety profile.
Severe side effects outweigh potential benefits.
FDA or other regulatory bodies may reject or halt development based on safety concerns.
82
Why is redundancy a reason for drug failure?
The new drug is too similar to existing therapies.
It offers no significant clinical advantage, making it less competitive or appealing to healthcare providers.
83
What role do corporate or financial issues play in drug failure?
Companies may lose interest or reorganize priorities.
Financial problems can halt funding needed for development and trials.
Strategic decisions may deprioritise certain drug candidates.
84
Why might a small market limit a drug’s development?
Rare diseases or orphan indications have fewer potential patients.
The potential return on investment may not justify high development costs.
Companies might withdraw if they foresee insufficient revenue.
85
What are examples of macromolecular therapeutics?
Macromolecules include recombinant proteins, oligonucleotides, and gene or gene-fragment therapies.
86
Why do small molecules still dominate the pharmaceutical market?
Over 90% of therapeutics in the market are small molecules.
As of 2014, 5 of the top-selling drugs were small molecules.
They continue to dominate pipelines due to established drug design models and manufacturing processes.
87
What are the key steps in a typical drug design model?
1. Find a lead compound.
2. Modify and study structure-activity relationships (SAR).
3. Identify the pharmacophore.
4. Create new analogues.
5. Optimize for the best therapeutic profile (efficacy, safety, PK, etc.).
88
How can observed clinical or pharmacological side effects lead to new drugs?
An existing drug’s side effect might suggest a new therapeutic use.
For example, sulfanilamide (an antibacterial) caused hypoglycemia, inspiring the development of tolbutamide (for Type II diabetes).
89
Why are natural products significant in drug discovery?
They’re a rich source of biologically active compounds.
Many current medicines are derived from, or inspired by, natural sources (e.g., plant alkaloids).
90
What role does traditional medicine play in finding lead compounds?
Traditional remedies often guide researchers to promising natural sources.
These can then be isolated, characterised, and optimised as modern drugs.
91
How do random screening and high-throughput screening (HTS) contribute to lead identification?
Large libraries of compounds (natural or synthetic) are tested rapidly.
Automation helps identify “hits” with desired bioactivity for subsequent optimization.
92
What is “combinatorial chemistry” and how is it used in drug discovery?
A technique to create large libraries of related compounds by systematically varying chemical structures.
Often paired with virtual or high-throughput screening to find potential leads quickly.
93
What are “Me too” and “Me better” drugs?
“Me too”: Structurally and therapeutically similar to existing drugs.
“Me better”: Retains core activity but is modified to bypass patent issues or enhance efficacy, safety, or pharmacokinetics (e.g., captopril → enalapril).
94
Why might a side effect be turned into a therapeutic effect?
If an existing drug produces a beneficial side effect, it can be optimized for that new indication.
Known pharmacokinetic and pharmacodynamic properties streamline development.
95
What is an example of using a side effect for a new drug indication?
Sulfanilamide’s hypoglycemic effect led to the creation of tolbutamide for Type II diabetes.
The side effect was harnessed and refined into a primary therapeutic action.
96
What are the two main approaches to drug discovery?
Ligand-based drug discovery – observes phenotypic effects of substances in biological systems to guide compound selection.
Target-based drug discovery – starts with a well-defined biological target and designs or screens compounds to interact with it.
97
What is ligand-based drug design?
It involves examining how substances affect biological systems (e.g., humans, animals, or cell cultures).
Observed phenotypic changes (e.g., reduced proliferation, behavioral shifts) suggest potential therapeutic effects.
These findings guide the optimization of lead compounds without necessarily knowing the precise molecular target initially.
98
What is phenotypic screening, and why is it important in ligand-based design?
Definition: Systematic testing of substances within a biological system to identify agents that produce a desired phenotypic outcome (e.g., reduced tumor growth).
Importance:
Can reveal novel mechanisms or targets not previously identified.
Does not require prior knowledge of the drug’s exact mode of action.
Has led to the discovery of many first-in-class drugs.
99
What is target-based screening?
Serial testing of compounds against an isolated biological target (e.g., a protein).
Aims to find substances that induce a desired biochemical outcome (e.g., inhibiting an enzyme’s catalytic activity).
100
Why is target-based drug discovery considered a “mechanistic” approach?
It starts with a rationally argued hypothesis about how a drug should act on a specific biological target.
Focuses on molecular details to guide lead discovery and optimization.
101
How does macromolecular crystallography support target-based design?
Provides the 3D structure of proteins and protein-ligand complexes.
Reveals conformational changes upon ligand binding.
Guides de novo design and lead optimization by showing how a ligand interacts with its target in precise detail.
102
What was the central assumption of target-based approaches in the 1990s?
Target-based methods would yield maximally selective compounds acting on individual targets, presumed to be safer and more effective.
103
What are some drawbacks of an exclusively target-based approach?
May overlook complex biological interactions not captured by a single target assay.
Can fail if the assumed target is not the only or primary driver of the disease.
104
How did drug discovery methods evolve from the 19th century to now?
Began as a largely serendipitous or phenotypic process.
Shifted toward high-tech target-based strategies in the 1980s–1990s.
Phenotypic approaches have made a recent comeback, delivering many first-in-class drugs.
105
What is the argument for combining target-based and phenotypic approaches?
Each method has complementary strengths.
Phenotypic screening can discover unexpected MOAs, while target-based design refines specific interactions.
Together, they may more effectively address complex diseases like cancer, diabetes, and AIDS.
106
Are we “coming full circle” in drug discovery?
Yes. Modern R&D increasingly uses both phenotypic and target-based strategies.
This integrated approach balances mechanistic insights with the potential for unexpected but beneficial effects revealed in phenotypic assays.
107
What is the main goal of drug (lead) optimization?
To maximize beneficial interactions at the target site (improve activity and selectivity)
To minimize side effects
To modify compound properties so the drug effectively reaches the target in the body
108
Why isn’t the compound with the strongest binding necessarily the best drug?
The drug must also overcome barriers to reach its target (absorption, distribution, stability).
It needs acceptable pharmacokinetic properties (metabolism, excretion) and safety.
109
How does structure-based drug design aid in lead optimization?
Uses X-ray crystallography and molecular modeling to see how a lead compound binds to its target.
Identifies molecular interactions that can be optimized for better efficacy and selectivity.
110
What are some strategies for modifying a lead compound’s structure (SAR)?
Varying substituents
Structural extension (adding functional groups)
Using isosteres or bioisosteres
Simplifying the overall structure
111
What are the three principal phases of drug action?
Pharmaceutical phase: Determines how much drug becomes available for absorption.
Pharmacokinetic phase: Influences how much drug reaches the site of action (ADME).
Pharmacodynamic phase: Determines the therapeutic effect once the drug engages its target.
112
What are the main “enteral” routes of drug administration?
Oral (swallowed)
Rectal (suppository)
Vaginal (pessary)
Buccal and sublingual (absorbed via the mouth’s mucous membranes)
113
What are common “parenteral” and other routes of administration?
Parenteral: Intravenous (IV), intramuscular (IM), subcutaneous (SC)
Other: Ocular (eye drops), nasal/pulmonary (inhaled), transdermal (topical patch/cream)
114
What are the main categories of dosage forms?
Liquid formulations: Solutions, suspensions, emulsions
Semi-solid formulations: Creams, ointments, gels
Solid formulations: Tablets, capsules
These forms require appropriate excipients to ensure stability and efficacy.
115
What does the pharmacokinetic phase involve?
Absorption: How the drug enters the bloodstream
Distribution: How the drug travels to and penetrates target tissues
Metabolism: How the body chemically alters the drug (e.g., liver enzymes)
Excretion: How the drug and its metabolites leave the body
116
Why is optimizing drug availability crucial in the pharmacokinetic phase?
Maximizes the fraction of drug that reaches the site of action.
Ensures sufficient concentration at the target for therapeutic effect.
Minimizes loss through premature metabolism or poor absorption.
117
What four key properties influence a drug’s ability to reach its target?
Hydrophilic/hydrophobic balance
Ionisation state
Molecular size
Chemical and metabolic stability
118
How do these properties affect a drug’s performance?
Solubility & permeability: Affected by hydrophobic/hydrophilic balance.
Absorption & distribution: Influenced by ionization and molecular size.
Stability: Determines how the drug withstands metabolic breakdown and reaches the target intact.
119
What is the first partition step a drug must undergo from the extracellular environment to reach its receptor?
Leaving the aqueous extracellular fluid.
The drug exits the water-based environment surrounding cells, preparing to cross into the lipid membrane.
120
What is the second partition step?
2. Crossing the lipid membrane.
The drug traverses the hydrophobic lipid bilayer, a process influenced by its lipophilicity, charge, and size.
121
What is the third partition step?
3. Re-entering an aqueous environment.
Once through the lipid membrane, the drug enters the intracellular or compartmental fluids where it can locate and bind its receptor.
122
What are potential problems related to drug metabolism?
Metabolites may lose activity (reduced therapeutic effect).
Metabolites can be more toxic than the parent drug.
Enzymatic variation (e.g., cytochrome P450 differences among patients) impacts drug efficacy and safety.
123
Why is understanding drug–receptor interaction crucial in pharmacodynamics?
Determines how effectively and selectively a drug binds to its target.
Influences therapeutic effect and side-effect profile.
Guides rational modifications of a lead compound (SAR studies).
124
What is the pharmacophore, and why is it important?
The pharmacophore is the essential three-dimensional arrangement of atoms or functional groups required for a specific biological activity.
Identifying the pharmacophore guides targeted modifications to enhance efficacy, selectivity, and reduce toxicity.
125
What is SAR, and how does it influence drug design?
Structure-Activity Relationships: Correlation of a molecule’s chemical structure with its biological activity.
Systematic SAR studies enable optimization of potency, selectivity, and ADME (absorption, distribution, metabolism, excretion) properties.
126
What is Lipinski’s Rule of Five?
No more than 5 hydrogen-bond donors (sum of OH and NH).
Molecular weight below 500 Da.
Log P (measure of lipophilicity) below 5.
No more than 10 hydrogen-bond acceptors (sum of N and O).
These guidelines suggest good absorption or permeation potential but do not guarantee pharmacological activity.
127
Why is keeping Log P low advisable in drug design?
Minimizes nonspecific binding and toxicity.
Improves formulation and bioavailability.
Facilitates better distribution and fewer off-target effects.
128
How do absorption, distribution, and metabolism affect drug action?
They can be as crucial as the drug’s direct biological effect.
Poor ADME properties can render a potent drug ineffective in vivo.
129
Why is lipophilicity and ionization state important for passive membrane transport?
Lipophilic, unionized molecules cross membranes more easily.
Ionized forms often struggle to diffuse through lipid bilayers.
Balancing these properties is key for optimal drug absorption.
130
Why is stereochemistry important in drug design?
Biological targets often differentiate between enantiomers.
One enantiomer may be more potent or safer than another.
Rational drug design must consider stereochemical requirements to enhance efficacy and reduce side effects.
