drug design

Question 1

What is meant by pharmacokinetics and give an example of codiene?

Answer 1

Pharmacokinetics refers to the study of how a drug is absorbed, distributed, metabolized, and eliminated by the body (ADME).

Absorption: Codeine can be administered orally, intravenously, or through other routes. When taken orally, it is well absorbed from the gastrointestinal tract and enters the bloodstream.

Distribution: Once absorbed, codeine is distributed throughout the body. It crosses the blood-brain barrier and can exert its effects on the central nervous system. Codeine also distributes into various tissues, including the liver.

Metabolism: In the liver, codeine is primarily metabolized by an enzyme called CYP2D6 to morphine, which is the active form responsible for the analgesic effects. However, the conversion of codeine to morphine can vary among individuals due to genetic differences in CYP2D6 activity. Some individuals are “poor metabolizers” and may experience reduced analgesic effects from codeine.

Elimination: The metabolized codeine (morphine) is further metabolized and eventually eliminated from the body through the kidneys via urine. The elimination half-life of codeine is typically around 2.5 to 3 hours. In individuals with impaired kidney function, the elimination may be slower.

Question 2

Describe the difference between Ligand-based drug design and targeted drug design with mention of selectivity and specificity?

Answer 2

Ligand based drug design is lead by finding a molecule that expresses the wanted pharmacological affect and without nessiarily knowing its target and using X-ray crystallography or computational modeling to determine its structure. At this point the structure is optimised from the lead molecule to test the potential of this pharmacological effect. This approach is selective for the effect however many targets can be activated to achieve the effect so it is not specific. Asparin is an example of this.

Target-based drug design, also known as rational drug design or direct drug design, involves identifying a specific target, such as a receptor or enzyme, that is involved in a disease process. The goal is to design compounds that selectively interact with the target and modulate its activity to achieve a desired therapeutic effect. This is specific as there is likely one target with multiple effects e.g HER2

Question 3

Define Agonist vs Antagonist in drugs.

Answer 3

An agonsit is a drug that mimics and reproduces a response similar to that of the naturally occuring biological molecule

An Antagonist is a drug that suppresses a naturally occuring response - opposite to agonist

Question 4

Give an example of a ligand-based drug development.

Answer 4

Asparin is a ligand based drug design as it was originally isolated from Willow bark
Salicin extracted, synthesised and optimised into Analogues and the mechanism of action was found later.

Question 5

Why are new drugs important?

Answer 5

Resotance, lowereing side effects, improving existing drugs, new targets and new diseases.

Question 6

Give an example of a drug that is neither specific or selective.

Answer 6

Antihistamines have many targets and many effects e.g drowsiness and dry eyes etc along with antihistamine effects.

Question 7

Why is it important to balance the primary and secondary effects of a drug with warfarin as an example?

Answer 7

Warfarin an anticoagulant has the potential to cause internal bleeding and has a small therapeutic window which is harmful to the patient so the risk needs to be tested by phenotypical tests of CYP2C9 to test pharmacogenetics capabilities of ultra vs slow metabolisers.

Question 8

Define a lead structure?

Answer 8

“In medicine, a chemical compound that shows promise as a treatment for a disease and may lead to the development of a new drug. This molecule may letter be optimised to produce the final drug.

Question 9

What is the goal of structural optimisation in drug development?

Answer 9

To increase Efficacy or potency

To reduce to toxicity and side effects - LD50

Increasing / reducing Polarity enabling solubility / Hydrophobicity changes to cross epithelial barriers and optimise distribution / bioavailability

Question 10

What important considerations are there for preclinical trails?

Answer 10

-LD50 needs to be useful for drug potency.
-Is the drug carcinogenic, teratogenic (birth defects)
-Proof of mechanism testing
-PD/PK
-Administration and the goal of the drug
Preclinical models mice and cell lines / yeast systems

Question 11

Give description of the 4 stages of drug clinical trails

Answer 11

Phase 1: In this initial phase, the drug is tested in a small group of healthy volunteers (usually 20 to 100 participants) to determine its safety profile, dosage range, and potential side effects. The primary focus is on assessing the drug’s pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics (how the drug affects the body). Phase 1 trials help establish a safe starting dose for further testing.

Phase 2: After successful completion of Phase 1, Phase 2 trials involve a larger group of participants (typically a few hundred) who have the condition or disease for which the drug is intended to treat. These trials assess the drug’s effectiveness in treating the targeted condition, optimal dosage, and further evaluate its safety. Researchers also gather more information about the drug’s side effects and risks. Phase 2 trials provide preliminary evidence of the drug’s efficacy and help guide the design of larger-scale studies.

Phase 3: Phase 3 trials involve a larger number of participants (ranging from hundreds to several thousand) and are conducted in multiple study sites or clinics. These trials are randomized and controlled, comparing the new drug to existing standard treatments or a placebo. The primary goal is to confirm the drug’s efficacy, evaluate its safety and side effects on a larger scale, and monitor long-term risks and benefits. Phase 3 trials provide critical data that support the submission of the drug for regulatory approval.

Phase 4: Also known as post-marketing surveillance or post-approval studies, Phase 4 trials occur after a drug has been approved and made available to the general population. These trials aim to gather additional information about the drug’s long-term safety, effectiveness in various patient populations, and potential rare side effects or drug interactions that may not have been detected in earlier phases. Phase 4 trials help ensure ongoing monitoring and evaluation of the drug’s benefits and risks in real-world settings.

Question 12

Define a pharmacophore?

Answer 12

Part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes.

Question 13

Give lipinski rule of 5 for drug design

Answer 13

Molecular Weight: The molecular weight of the compound should be less than 500 daltons.

Lipophilicity (LogP): The logarithm of the partition coefficient (LogP) should be less than 5. A higher LogP indicates higher lipophilicity.

Hydrogen Bond Donors: The molecule should have no more than 5 hydrogen bond donor groups (such as OH or NH groups).

Hydrogen Bond Acceptors: The molecule should have no more than 10 hydrogen bond acceptor atoms (such as oxygen or nitrogen atoms).

Question 14

How do competitive inhibitor drug block tyrosine kinase g couples receptors and protein kinases?

Answer 14

Protein kinases require ATP (adenosine triphosphate) as a co-substrate for their catalytic activity. Competitive inhibitors can structurally resemble ATP and bind to the ATP-binding site on the kinase. By doing so, the inhibitor competes with ATP for binding, preventing the kinase from accessing ATP and inhibiting its phosphorylation activity.Protein kinases require ATP (adenosine triphosphate) as a co-substrate for their catalytic activity. Competitive inhibitors can structurally resemble ATP and bind to the ATP-binding site on the kinase. By doing so, the inhibitor competes with ATP for binding, preventing the kinase from accessing ATP and inhibiting its phosphorylation activity.

Tyrosine kinase G-coupled receptors are a specific type of cell surface receptor that, when activated, initiate signaling pathways that involve protein kinases. Competitive inhibitors can interfere with the activation of these receptors by binding to the receptor’s ligand-binding site. This blocks the activation through GDP to GTP binding.

Question 15

Regarding bonding what needs to be considered when designing a drug?

Answer 15

Which type of bond exists within the target e.g Ionic electrostatic etc. designing based on this will produce stronger binding. Additionally, isomers as the drug may have the same chemical formula but different structures affecting binding or giving unexpected results for binding.

Question 16

What kind of structural changes would be needed to affect solubility in a drug?

Answer 16

Increased polarity through OH and ionisable centre.

Question 17

Give a drug example for ligand-based drug design.

Question 18

What is a drug target ? examples of drug targets ?

Answer 18

A drug target refers to a specific molecule or biological structure that is the intended site of action for a drug.

G-protein-coupled receptors (GPCRs): GPCRs are a large family of cell surface receptors involved in transmitting signals from outside the cell to the inside. They are targeted by numerous drugs to modulate various physiological processes. Examples include beta-adrenergic receptors targeted by beta-blockers and serotonin receptors targeted by selective serotonin reuptake inhibitors (SSRIs).

Protein kinases: Protein kinases are enzymes that phosphorylate proteins and play crucial roles in cellular signaling. Many diseases, including cancer, are associated with dysregulated kinase activity. Drugs targeting specific protein kinases, such as tyrosine kinases, are used for cancer treatment. For example, imatinib targets the BCR-ABL tyrosine kinase in chronic myelogenous leukemia.

Enzymes: Enzymes catalyze biochemical reactions in the body, and inhibiting specific enzymes can interfere with disease processes. For instance, statins target HMG-CoA reductase, an enzyme involved in cholesterol synthesis, to lower cholesterol levels.

Ion channels: Ion channels are integral membrane proteins that regulate the flow of ions across cell membranes. They play essential roles in processes like nerve signaling and muscle contraction. Drugs targeting ion channels can modulate these processes. For example, calcium channel blockers target calcium channels to reduce blood pressure.

DNA or RNA: Nucleic acids, such as DNA or RNA, can be targeted by drugs for therapeutic purposes. Anticancer drugs, like cisplatin, form covalent bonds with DNA to inhibit DNA replication and induce cell death.

Antibodies: Monoclonal antibodies are designed to bind to specific antigens, such as proteins or cell surface receptors. They can target various diseases, including cancer, autoimmune disorders, and inflammatory conditions. Examples include trastuzumab, targeting the HER2 receptor in breast cancer, and adalimumab, targeting tumor necrosis factor-alpha (TNF-alpha) in autoimmune diseases.

Question 19

What are the different approaches to drug discovery ? Traditional and contemporary

Answer 19

Traditional Approaches:
a. Natural Product Discovery: Historically, many drugs were derived from natural sources such as plants, fungi, and microorganisms. Scientists would isolate compounds from these sources and screen them for pharmacological activity.
b. High-Throughput Screening (HTS): This approach involves the rapid screening of large libraries of synthetic or natural compounds against specific drug targets. It relies on automated systems and robotics to test thousands to millions of compounds for activity, narrowing down potential hits for further development.
c. Structure-Based Drug Design: This approach utilizes the knowledge of the three-dimensional structure of a target protein to design molecules that can bind to and modulate its activity. Computational modeling, including techniques like molecular docking and virtual screening, is often employed to predict and optimize drug-target interactions.

Rational Drug Design: With advancements in computational biology and structural biology, scientists can use computer-aided drug design techniques to identify and optimize drug candidates. This approach combines molecular modeling, virtual screening, and computational simulations to design compounds with desired properties.
c. Fragment-Based Drug Design: Instead of screening large compounds, this approach focuses on smaller, low-molecular-weight fragments. Fragments that bind to the target protein are identified and then chemically optimized to develop more potent drug candidates.
d. Phenotypic Screening: Instead of targeting a specific protein or pathway, phenotypic screening involves testing compounds for their effects on whole cells or organisms. This approach allows for the discovery of drugs that modulate complex disease-related phenotypes, regardless of the underlying molecular target.
e. Repurposing/Repositioning: This approach involves finding new therapeutic uses for existing drugs that were originally developed for different indications. By leveraging existing safety and toxicity data, repurposing allows for faster and potentially cost-effective drug development.

Question 20

What do we mean by Hit to lead identification/discovery ? What is the goal ?

Answer 20

hit to lead discovery” refers to the process of selecting and optimizing potential drug candidates from a pool of initial hits obtained through screening assays or other discovery methods. The goal of this stage is to identify a lead compound or a small set of compounds that exhibit promising activity against a specific target or disease pathway, and then further develop and optimize them into potential drug candidates.

Question 21

How can we optimise a lead compound?

Answer 21

Through replacement of functional groups to change solubility, permeability, efficacy and potency

Question 22

How do we carry out preclinical testing of compounds? Benefits of in vivo vs in vitro testing ?

Answer 22

Preclinical testing is an essential step in the drug development process that involves evaluating the safety, efficacy, and pharmacokinetic properties of potential drug candidates before they can proceed to clinical trials in humans. Preclinical testing is typically conducted using in vitro (cell-based) and in vivo (animal-based) models.

In Vitro Testing:

In vitro testing involves studying the effects of the compound on isolated cells or cellular components in a controlled laboratory setting.

in Vivo Testing:

In vivo testing involves evaluating the compound’s effects in living organisms, typically animals, to provide a more comprehensive understanding of its pharmacokinetics, efficacy, safety, and potential toxicities.

Question 23

What do we mean by a receptor ? what is an orphan receptor ?

Answer 23

Receptor refers to a specific molecule or protein on a cell surface or within a cell that binds to specific ligands, such as hormones, neurotransmitters, drugs, or signaling molecules.

An orphan receptor refers to a type of receptor whose natural ligand or specific function has not been identified or characterized yet.

Question 24

What are the typical properties of a small molecule drug?

Answer 24

Rapid diffusion, cheaper

Question 25

Define potency and efficacy and how they affect the shape of the drug response curve

Answer 25

Potency refers to the concentration or dose of a drug required to produce a specific effect. It represents the drug’s strength or activity at a given receptor or target.

Efficacy refers to the maximum effect or response that a drug can produce, regardless of the dose or concentration. It represents the drug’s ability to elicit a therapeutic effect or desired outcome

Question 26

What do we mean by IC50, GI50, ED50, LD50 ?

Answer 26

IC50 (Inhibitory Concentration 50%):
IC50 refers to the concentration of a drug or compound that is required to inhibit a specific biological process or target by 50%.

GI50 (Growth Inhibition Concentration 50%):
GI50 is a measure of the concentration of a drug or compound required to inhibit the growth of cells, typically in cell-based assays or in cancer research.

ED50 (Effective Dose 50%):
ED50 is the dose or concentration of a drug that produces a specific therapeutic effect in 50% of the individuals or experimental subjects tested.

LD50 (Lethal Dose 50%):
LD50 refers to the dose or concentration of a drug or compound that is lethal and causes death in 50% of the individuals or experimental subjects tested.
It is a measure of acute toxicity and is typically determined in preclinical studies using animal models.

Question 27

What are agonists and antagonists and what effect do they have on a dose response curve
in terms of potency and efficacy?

Answer 27

Agonists:
Agonists are drugs or compounds that bind to a specific receptor and activate it, producing a biological response.

Agonists have potency, which refers to their ability to produce a response at a given concentration or dose. A more potent agonist requires a lower concentration or dose to produce a given effect compared to a less potent agonist.
Efficacy: Agonists also have efficacy, which refers to their ability to produce a maximal response. Highly efficacious agonists produce a maximal response, even at low concentrations or doses. The shape of the dose-response curve for agonists is characterized by a steep ascent and a plateau where further increases in concentration or dose do not produce additional response.

Antagonists:
Antagonists are drugs or compounds that bind to a specific receptor without activating it, blocking the binding of agonists and inhibiting the receptor’s activity.

Potency: Antagonists have potency, representing their ability to bind to a receptor. Potency is determined by the affinity of the antagonist for the receptor. A more potent antagonist requires a lower concentration or dose to occupy the receptor and exert its blocking effect compared to a less potent antagonist.

Efficacy: Antagonists do not have efficacy as they do not produce a response. They shift the dose-response curve of an agonist to the right, resulting in a decrease in the potency of the agonist without affecting its maximal response. The shape of the dose-response curve for antagonists is typically flat and parallel to the baseline, indicating that increasing concentrations or doses of the antagonist do not produce a response.