3 + 4 Flashcards
Why are lead structures modified?
So that binding interactions between a drug and its target are improved.
What does stronger binding do?
- Lead to greater activity
- Increase selectivity.
Stronger binding to a certain target will improve the selectivity between different targets.
The better the binding to our target, the less we have to worry about it binding to other things.
Explain Alkyl substituents in terms of variation?
Alky groups bound to heteroatoms can be easily varied.
Alkyl groups bound to carbon atoms CANNOT be easily removed and replaced – so a modified full synthesis may be required
The enlargement of an alkyl substituent may lead to stronger binding to such a region.
The overall size may also improve the selectivity of a drug
Explain Aromatic substituents in terms of variation?
Relatively easy to vary the position of substituents on an aromatic ring.
Changing the position of one substituent may affect the electronic properties of another, if they become ortho or para substituted to one another.
Explain Chain Extensions, Ring Expansions, Ring Variation, and Extension by Ring Fusion?
(Structure Extension)
Chain Extensions / Contractions:
If a lead structure has two binding groups linked by a chain, the length may not be ideal for optimum binding to both sites. Varying chain length may improve drug-target interactions.
Ring Expansions / Contractions:
Altering the size of a ring will affect the orientation of substituents – the same effect as varying substituent pattern.
Binding groups may end up in a better position to bind to the binding site
Ring Variation:
A common strategy employed during analogue synthesis is to replace an aromatic ring with a different heteroaromatic ring This may result in extra hydrogen bonding with the binding site
Extension by Ring Fusion:
A lead structure can also be extended by fusing one ring onto another.
This may introduce selectivity (as in the case of alkyl chain extensions) and also allow for extra van der Waals interactions
Explain how Structural Simplification takes place?
Identification of the pharmacophore can allow us to simplify the structure of analogues, so that they contain only the essential binding regions – makes the synthesis of analogues easier.
What are some negative effects of Structural Simplification?
Change in activity:
Drastic changes may result in analogues that bind differently leading to different effects.
Loss of selectivity:
Simplification may also result in reduced activity and selectivity. Flexible molecules may bind with a number of similar receptors.
Simplification is only useful if the lead is a complex natural target.
Explain Structural Rigidification?
What is the disadvantage of this?
- Locking a molecule into only one conformation by rigidification may improve selectivity
A common strategy is to discover the active binding conformation and then rigidify by incorporating the skeleton into a ring
The disadvantage of this strategy is that the drug targets may be difficult to synthesise
Examples of Rigid functional groups?
Rings, amides, aryl groups and alkynes.
What is the ‘QUANTITATIVE STRUCURE-ACTIVITY RELATIONSHIPS’ (QSAR) approach?
it is attempted to derive a mathematical relationship between physicochemical parameters and biological activity in the form of an equation.
What can the QSAR equation be used to do?
- Predict in advance the activity of an unknown compound
- Derive a structure that exhibits optimum activity. The medicinal chemists knows which type of analogue to prepare; this will cut down on the cost and time taken to develop a drug
- Discover which drug properties have an important role. This may give us information regarding the nature of the active site of an enzyme/receptor
How is partition coefficient measured and why?
Used to determine Hydrophobicity and Lipophilicity.
Measured by investigating a drug’s distribution in an octanol/water mixture.
P = Concentration of drug in octanol / Concentration of drug in water
What are the three stages of drug action?
- Transport of the drug to its site of action
- Stability of the drug
- Binding of the drug to the target active sit
What does each stage of drug action depend on?
Stage 1 – depends largely on membrane permeability – drug’s lipophilicity
Stage 2 – depends on stability – ionisation potential
Stage 3 – depends on the size of a drug and the configuration of the structure.
Equation for Biological Activity?
Biological Activity = lipophilicity + stability + binding
What does the electronic effects of a substituents affect?
The acidity/basicity of aromatic compounds.
What is the Hammett Substitution Constant?
The Hammett substitution constant (σ) is a measure of the electron withdrawing or donating properties of a substituent - calculated for aliphatic and aromatic compounds.
Takes into account both resonance and induction.
Electron donating substituents - σ negative
Electron withdrawing substituents - σ positive
What is The molar refractivity (MR)?
A measure of molecular volume that also takes into account the polarizability of the electron cloud in the molecule
What are the steps of Rational Drug Design?
Identify target disease
Identify and validate drug target
Establish screen
Find a lead compound
Structure Activity Relationships (SAR)
Identify the pharmacophore
Drug design - optimising target interactions
Drug design - optimising pharmacokinetic properties
Preclinical trials
Chemical development and process development
Patenting and regulatory affairs
Clinical trials
What is the purpose of Rational Drug Design?
To increase activity and reduce dosage required
To increase selectivity and reduce side effects
What are the strategies for rational drug design?
Vary alkyl and aryl substituents
Chain extension and contraction
Ring expansion, contraction and variation
Isosteric and bioisosteric replacements
Simplification
Rigidification
What is Isosteric?
What is Bioisosteric?
Isosteric - Replacing one functional group, with another – changes activity
Bioisosteric - You maintain the activity
Isosteric replacements are used to affect the activity of compounds IN VITRO, i.e. in cultured cells
Whereas Bioisosteric replacements are used to monitor activity IN VIVO, i.e. in animal models.
Explain the structure of an Angiotensin Converting Enzyme?
Has two different sheet like regions
Has residues
There is a zinc atom, within the active site of the enzyme
What is the difference between primary and secondary Hypertension?
Primary: No obvious cause though family history, smoking, alcoholism or obesity may predispose a patient
Secondary: Well-defined condition that can be identified: renal disease; tumours; drug side-effects; pregnancy
Explain the Reflex Control of Blood Pressure?
Baroreceptor mechanism:
- Pressure sensing areas throughout vasculature
- Alters the autonomic outflow; raises or lowers your blood pressure
- Continuous monitoring, fast response
What is the Renin-angiotensin system?
A long term control of pressure
What is Renin?
A proteolytic enzyme.
Secreted from the juxtaglomerular cells (kidney).
How is Renin secretion increased and inhibited?
Renin secretion is increased by:
- A fall in Na+ concentration
- A fall in renal perfusion pressure
- b-adrenoceptor agonists
- Prostacyclin
Renin secretion is inhibited by:
- Angiotensin II (feedback control)
- Atrial natriuretic peptide
Explain the Renin-Angiotensin System?
Renin, a proteolytic enzyme, is secreted into the blood by the kidneys by the juxtaglomerular apparatus
Angiotensinogen is produced by the liver
Renin cleaves angiotensinogen to give angiotensin I
Angiotensin Converting Enzyme (ACE) cleaves angiotensin I, to give angiotensin II, during passage through the lungs
Angiotensin II constricts the renal efferent arteriole greater than the afferent arteriole
Angiotensin II increases or maintains the glomerular filtration pressure – affects the filtration levels and responses within the kidney.
Increased angiotensin II levels is often a physiological response to renal artery stenosis
What are the roles of Angiotensin II?
Increases the activity of the heart
Affects the release of aldosterone, which effects the retention of water
It affects electrolytes
It is a vasoconstrictor - increases pressure (blood pressure)
Affects the pituitary gland causing ADH secretion
What is Angiotensin Converting Enzyme (ACE) ?
What are its functions?
Endothelial cell membrane-bound glycoprotein.
Functions:
- ACE creates angiotensin II
- ACE inactivates bradykinin
- Inhibition of ACE should lower blood pressure
Summary of the Renin-Angiotensin System?
Why is this system important?
Angiotensinogen, makes Angiotensin I, when mixed with renin. Renin chops some structures of the reactant.
Then Angiotensin I is mixed with ACE to make Angiotensin II
Then II is mixed with Aminopeptidase to make Angiotensin III
This system critical for blood pressure control
What types of enzymes are ACE and Carboxypeptidase A ?
What are the structure?
Both enzymes are exopeptidases: they cleave residues from the ends of a protein
Both enzymes require a free C-terminal CO2H
The active site of both enzymes contains zinc
