Dugga 2 Flashcards
Why do many drugs contain an amine functional group?
They are partially ionised in the acidic environment of the stomach and the slightly alkaline environment of the blood but can cross cell membranes (such as intestinal cell membrane) in their non-ionised form. The ionised form gives a good water solubility and good binding interactions
Some highly polar drugs are able to cross cell membranes, how?
They can hijack transport proteins if the resemble the polar molecule that is usually transported. An example is levodopa which disguises as phenylalanine
Some small highly polar drugs are able to pass cell membranes, how?
They pass through small pores between the cells lining the gut
Polar drugs with high molecular weight can pass cell walls by a process called…
pinocytosis - the drug is engulfed by the cell membrane and carried in a membrane bound vesicle
What is pharmacodynamics?
How drugs interact with molecular target o produce a pharmocological effect
What is pharmacokinetics?
How a drug reaches its target in the body and how it is affected on the journey
What are the four main issues in pharmacokinetics?
ADME
Absorption Distribution Metabolism Excretion
Oral drugs must be sufficiently … to dissolve in the GIT and blood but sufficiently … to pass cell membranes
polar and fatty
Oral drugs have to be both … and … stable
chemically and metabolically
How many rotatable bonds do oral drugs usually have (max)
7
Does Lipinski’s rule apply to only oral drugs?
Yes
What may happen to some drugs that mean they won’t be active?
Absorbed in fatty tissue or bound to macromolecules
Do some drugs make use of metabolism to active?
Yes
Which reactions do phase I reactions involve?
Oxidation, reduction, hydrolysis
What structures are most prone to oxidations?
N-methyl groups, aromatic rings, terminal positions of alkyl chains, least hindered positions of alicyclic rings
What groups are prone to reduction?
nitro, azo (N=N) and carbonyl groups
What groups are prone to hydrolysis?
amides O=C-N) and esters (O=C-O)
What are phase II reactions?
Conjugations with polar groups on an already existing handle
When can oxidation of carbon occur?
If it is exposed or activated. Activated carbons next to sp2 or sp carbon centre most likely, carbons alpha to heteroatoms.
When do you have to think about first pass effect?
With oral drugs. They need to pass the cell lining of the intestine to move to the blood and also go through the liver
What is metabolism?
How our body makes compounds more water soluble for excretion. First oxidation, hydrolysis to create a handle, then conjugation with polar molecules
How do you avoid first pass effect?
Administer drugs in another way than orally
What is phase 1 metabolism?
The addition of or exposure of polar functional drugs. Cytochrome p450 enzymes break down.
How is the activity of CYP450 affected?
By food, chemicals and drugs
How does drug excretion take place?
Sweat, inhaled air, bile and mostly kidneys
What does the kidney do?
Filters the blood and drugs and their metabolites enter nephrons. Non-polar substances reabsorbed into blood but polar substances excreted in the urine.
How can safe dosing levels for a drug be determined?
Measurements of concentration of drug in the blood
What is therapeutic index
Area between efficacy level and toxic level
What is the half life of a drug?
Time taken for the concentration of drug in blood to fall to half
The time it takes to reach steady state concentration is … times the drugs half life
6
What is AUC?
Area under the plasma drug concentration curve represents total amount of drug available in the blood supply
How do you ensure the blood concentration of a drug remain within the therapeutic window?
Administer at correct dose and frequency
Can the half life of a drug be used to calculate how frequently a dose should be given?
Yes
What is a statin?
Cholesterol lowering drug acts as enzyme inhibitor
Where are type 1 statins derived from?
Fungal metabolites
Why do statins bind more strongly than natural substrate to the enzyme responsible for biosynthesis of cholesterol?
- An extra hydrophobic region forms additional hydrophobic interactions
- resistant to enzyme catalysed reactions
What is HTS and how can it be used?
High throughput screening involves the miniaturisation and automation of in vitro tests. A large number of tests can then be carried out in a short space of time
What is NMR and how is it used?
Nuclear magnetic resonance. Compounds affinity to a macromolecular target tested by NMR. The relaxation times of ligands bound to macromolecule shorter when they are unbound.
What is SPR, SPA and ITC and how can it be used?
Surface plasmon resonance, scintillation proximity assay, isothermal titration calorimetry are visual methods of detecting whether a ligand is bound to a macromolecular target
How can virtual screening be used?
To identify compounds that are most likely to be active in an experimental screening
What is a lead compound?
A compound that shows the desired pharmacological activity
Where can a lead compound be found in nature?
Plants (eg antimalaria drug), Microorganisms (penicillin), marine (antitumor agents), animals (antibiotic polypeptide from frog), venoms and toxins (antihypertensive agent)
What is an analgesic drug?
For pain relief
What are different ways to find lead compounds?
Nature,medical folklore, screening synthetic compounds, improving existing drugs, starting from natural ligand or modulator, computer aided design, serendipity
What is the agent responsible fir the biological activity of a natural extract called?
The active principle
What is a lead compound?
A structure that shows a useful pharmacological activity and acts as the starting point for drug design
How can the ability to crystallise a molecular target and the use of x Ray crystallography help in designing drugs?
Can help to design lead compounds that will fit the binding site
What type of bonding is alcohols and phenols usually involved in?
Hydrogen bonding
Can the OH group act both as a HBA and a HBD?
Yes hydrogen as HBD and the two lone pairs on oxygen as HBA
If we change an OH group to a methyl ether O-Me or methyl ester O-C=O-Me analogue are we likely to lose the hydrogen bond?
Yes, the hydrogen will nolonger act as HBD, the oxygen could act as HBA but is likely sterically hindered, so the ability to form hydrogen bond is weakened.
Which binding is aromatic rings typically involved in?
Van der Waals interactions. Aromatic rings are flat so an analogous cyclohexane that isn’t flat would act differently
What type of binding does alkenes have?
Van der Waals
What type of binding does ketone have?
Can form two hydrogen bonds with the two lone pairs of electrons on oxygen. Dipole dipole is also possible. It is easy to reduce ketone to alcohol which will change it from flat to tetrahedal
How do amines bind?
Hydrogen bonds. Can act both as HBD and HBA. One lone pair of electrons.
Aromatic and heteroaromaric amines can only act as HBD because lone pair interacts with aromatic ring
What binding can a protonated amine have?
Only HBD because it doesn’t have its lone pair available. But also ionic bonds
What is an amine?
N, can be primary (bound to two H), secondary (bound to one H) or tertiary (not bound to any H)
What is an amide?
N-C=O
What binding does amides do?
Hydrogen bonds. Oxygen two lone pairs act as HBA. N cannot be HBA because lone pair interacts with carbonyl. N can be HBD (if primary or secondary amide)
What is a Lactam?
An amide in a ring system
What is a known structure containing a beta lactam ring?
Penicillin
How does a carboxylic acid bind?
HBA/HBD
May exist as carboxylate ion so ionic interactions
What binding does ester do?
HBA. The carbonyl oxygen most likely, the alkoxy oxygen more sterically hindered
What are esters susceptible to?
Hydrolysis by esterases
How are esters used in prodrugs?
To mask carboxylic acid, alcohol or phenol to achieve better absorption in GI, ester is then hydrolysed
What is cox?
An enzyme called Cyclooxygenase required for prostaglandin synthesis
How do alkyl halides bind?
Halide ion is a good leaving group so alkylation reaction by nucleophilic attack. Can be dangerous and drugs containing such groups usually reserved for life threatening diseases. C-F not easily broken
Binding role ethers
ROR act as HBA
In an aromatic ether O is a bad HBA
How many electrons involved in aromatic ring pi bonds?
6
If a heteroatom is part of it its lone pair is involved and so not available to form hydrogen bonds
What are isosteres?
Groups of atoms that share the same valency and chemical or physical similarities
Give an example of isosteres of OH
SH, NH2, CH3
Give an example of isosteres of O
S, NH, CH2
How can you use isosteres?
To determine if a particular group is an important binding group
What is pharmacophore?
It identifies the important binding groups required for activity and their position in space with respect to each other
Can be 3D and only focus on bonds
More flexible structures pharmacophore is more difficult to determine, why is that?
Because of all the different conformations it can take. The active conformation is the name given to the confirmation that the molecule has when active
What is SAR?
Structure activity relationship
What does SAR do?
Defines the functional groups or regions of a lead compound that are important in biological activity
How can the relevance of a functional group for binding be determined?
By preparing analogous where the functional group is modified
Once a pharmacophore has been established, what is next?
Synthesising analogous that contain same binding groups in order to optimise the drug. For instance by varying the substituents or extending the structure or simplifying the structure or rigidifying the structure
Why might you want to replace a methyl group with an isopropyl group on a drug?
To fill a hydrophobic pocket in the active site and thus have better binding interactions and possibly create a selectivity for one receptor over another
What is often used as an isostere of hydrogen?
Flourine
What are bioisosteres commonly used as in drug design?
To replace a problematic group while retaining activity
What is a pyrrole ring?
A five ring with N and its aromatic
What steps of simplification of a drug structure might be useful to consider?
Removing assumetric centres
Simplifying the carbon skeleton
Why would you want to avoid carbon centres in a drug?
Because enantiomers of a drug can have different activity, one example is thalidomide
Give an example of a way to remove a carbon Centre in a drug
Replacing the carbon Centre with nitrogen. However this may have significant effects in pharmacokinetics in terms of logP, basicity and polarity
Give an example of how to avoid carbon centres in drugs
Make a drug symmetrical so that both enantiomers are the same
What is the conformation recognised by the receptor known as?
The active conformation
What is the purpose of rigidification of a drug?
To retain the active conformation
Does a rigid molecule have a better binding affinity?
Yes
What ways are there to rigidity a rotatable bond?
Locking it into a ring
Double bonds
Incorporating alkyne, amide, aromatic ring
What is a conformational blocker?
Introduction of a group that makes a steric clash so that the rotation is nolonger possible
What is structure based drug design?
A target protein is crystallised with a ligand bound to the binding site. Then x Ray crystallography is used to determine the structure of the complex and downloaded to the computer. That can be used to see where the ligand is and identify binding site. The ligand can be removed in silico (on the computer) and new compounds inserted in silico to see how they fit
What is de novo drug design?
Design of a drug structure based on knowledge of the binding site
What is important when designing a drug?
Binding
That synthesis is possible
That it will reach its target
What is multi target drug discovery?
When you want to design a drug that interact with different targets to avoid having to take a cocktail of drugs
What are two strategies to make a multi target drug discovery?
Individual drugs linked together to form dimeric structure
Designing a multi target drug from a lead compound that interacts with wide variety of targets (a promiscuous ligand or dirty drug)
What are important aspects of a drug’s pharmacokinetics?
Being absorbed into the blood supply
Reach the target efficiently
Be stable enough to survive the journey
Be eliminated in a reasonable period of time
How do we measure hydrophobicity?
Log P value, how a drug distributes itself in an octanol/water phase
What is the issue with highly polar drugs?
Cannot cross cell membranes so cannot be given as oral drugs
Can be injected but will still not be able to cross cell membranes so cannot be used for intracellular targets
Polar functional groups can cause them to bind to plasma proteins, be phase II metabolised and excreted rapidly
What is the issue with highly hydrophobic drugs?
Likely to be dissolved in fat globules in the blood and be poorly absorbed
If injected they will be taken up by fat tissue
Drugs can exist in a equilibrium between an ionised and an unionised form, will logP measure both?
No, logP only measures the unionised form
LogD measured both the ionised and the unionised form
How can you decrease polarity?
By masking polar functional groups. Often the polar groups are needed for binding and so you only mask them temporarily so that the mask is removed when absorbed (a prodrug)
How can you change the polarity of a drug?
Masking polar groups
Removing polar groups if not needed
Adding hydrophobic groups
What should pka of a drug be between?
6 - 9
How can you vary pka?
Varying N-alkyl groups which have increased electron donating effect which increases basicity
How can the pka of an aromatic amine or carboxylic acid be varied?
By adding electron donating or electron withdrawing substituents
Mention a way to make a drug more resistant to chemical and enzymatic degradation
Adding a steric shield
Mention two approaches to avoid metabolic degradation by using metabolic blockers
Fluorine can be added as a substituent to block metabolism
Replacing a hydrogen with deuterium which has a covalent bond twice as strong as hydrogen
How can you make an aromatic ring less susceptible to metabolism?
Introduce a nitrogen atom into the aromaticbring can lower electron density and make methyl substituent more resistant to metabolism
If a drug stays in the body for too long you might want to make your drug more susceptible to metabolism, how?
Introducing metabolically susceptible groups
Self destruct drugs are stable under one set of conditions but not another, for instance stable in acidic pH bit not the slightly alkaline conditions of the blood
What does a steric shield do?
It protects susceptible (to metabolism) functional groups
How can you target cancer drugs?
By attaching active drug to an important building block molecule that is needed in much larger amount by a dividing tumor cell
A new idea to attach active drug to monoclonal antibody recognising antigens unique to tumour cells
What functional groups are commonly used as prodrugs?
Esters cleaved by esterase
N-methylation by N-demethylation
What are different reasons for making prodrugs?
Improve cell membrane permeability (levodopa)
To prolong drug activity (antimalarial agent)
To mask drug toxicity and side effects (salicylic acid)
To avoid bad taste (by lowering water solubility)
To improve water solubility (to make injections hurt less)
To increase chemical stability
To be activated by external influence (photodynamic therapy)
What is a sentry drug?
A second drug that is administered to guard or assist another drug (carbidopa is an example of an enzyme inhibitor that helps levodopa)
Why can the body’s own neurotransmitters not be synthesised and used?
Because they act on many different receptors since they are only released locally, but a drug needs to be able to travel the body and reach the right receptor. They might also be addictive
Some of the body’s own hormones are used as drugs, give examples
Insulin, human growth factor, adrenaline
