QSAR and drug design (DONE) Flashcards
What is QSAR?
Quantitative Structure Activity Relationships
An alternative method for drug design
Predicts compounds to synthesise and increases the efficiency of the drug design process
Properties that are considered when designing a drug
Intrinsic- molecular weight, H bonding, surface area
Physicochemical- steric, electronic, hydrophobic
Biological- activity, metabolism
How does QSAR predict compounds to synthesise?
By establishing a mathematical relationship between biological activity and a measurable property of the drug
Assumptions made by QSAR
Drug activity =f(drug structure)
A lead compound is required and only structurally related drugs e.g. those with a common pharmacophore can be compared
Can only be used to develop a single lead compound
Limitations of QSAR
Cannot be used for lead compound identification, but is effective for lead compound optimisation
Frequently used to analyse various substituents around a core structure
Potential drugs must have same mechanism of action and same chemical backbone/ pharmacophore
A quantitative measure of both activity and drug properties is required
Substituent effects in QSAR
Lots of substituent properties have been used in QSAR studies but the most commonly encountered are hydrophobic, steric and electronic
The physchem properties of substituents can have a large effect on the activity of a drug
How does QSAR compensate for substituent effects?
QSAR attempts to quantitatively determine how each of these properties affects the biological activity of a drug and derive a mathematical equation to describe the relationship
Hydrophilicity and P
The hydrophobic nature of a drug is vital to its ability to cross cell membranes, also affects water solubility, bioavailability, target interactions, non-specific binding etc.
Described by the partition coefficient, P
P= concentration of drug in octanol/ concentration of drug in water
Hydrophobic compounds have a high P value
Hydrophilic compounds have a low P value
Hydrophobic drugs: general anaesthetics
The activity of very few drugs is related to one physchem factor alone. General anaesthetics are an exception, as lipophilicity is the major factor governing their biological activity
The substituent hydrophobicity constant, pi
Within a series, partition coefficients (P) are measured for compounds with (X) and without (H) a substituent
Positive values for pi indicate hydrophobic substituents
Negative values for pi indicates hydrophilic substituents
Electronic factors
Electronic factors can dictate how polar a drug is, how easily it is ionized, and how strongly it binds to enzymes or receptors
A substituent’s electronic effect on an aromatic ring can be quantitatively described by the Hammett substitution constant
This is a measure of the electron donating or electron withdrawing ability of a particular substituent
Hammett constants positions
Hammett constants take into account whether a substituent is meta or para on a benzene ring
Ortho substituents exert strong steric effects and are not included :(
What affects the value of the Hammett substitution constant?
Electronic effects are usually stronger in para substitution patterns compared to meta substitution
Electron withdrawing groups usually give positive values
Electron donating groups usually give negative values
Relatively, the larger the number the stronger the effect
Steric factors
Steric factors are a measure of bulkiness of a group
A bulky substituent may not be able to approach an enzyme or receptor
Alternatively, a bulky group could increase target binding by correctly orientating the drug within its target active site
Taft’s steric factor quantitatively describes the size of a substituent relative to the methyl group
All values are negative compared to the methyl group which equals zero
The larger the negative number, the more bulky the substituent
The Hansch equation
It gives a quantitative measure of drug activity, using quantitative substituent constants, and can be in terms of:
Partition coefficient, P
Substituent hydrophobicity constant, pi
Hammett substituent coefficient, sigma
Tafts steric factor, Es
as well as any other physicochemical property that can be quantified
Two forms of the Hansch equation
For small ranges of P, the equation is linear
For large ranges of P, the equation is a parabola
The constants are solved by a statistical software that calculates the best fit of the line
Once obtained, the equation can be used to predict new compounds to synthesize
The Craig Plot
Tables of data are available for QSAR, but the Craig Plot is a useful method to compare different substituents. A glance can tell us the properties of various substituents
Everything on a vertical line will have similar electronic properties
Everything on a horizontal line will have similar polarity
What else dose the Craig Plot tell us?
There is no overall relationship between lipophilicity and electronic factors
It is easy to see substituents with similar properties
Once a Hansch equation has been derived, and the relative contribution from a quadrant determined, the Craig Plot indicates which substituents to incorporate into a drug
The Topliss Scheme
When time or economic restraints limit the number of compounds that can be synthesized, a full Hansch analysis may not be possible
The Topliss scheme is a flow diagram, designed for rapid optimisation of hydrophobic and electronic factors
There are two Topliss schemes, one for aromatic substituents and another for aliphatic groups
Assumption: the lead compound has been identified and contains a monosubstituted aromatic ring (or aliphatic group)
What is the rationale behind the Topliss scheme?
Each branch of the Topliss scheme has been carefully chosen to compare and contrast pi and sigma
Studies have shown the Topliss scheme to be very effective in accelerating drug design and minimising the number of compounds synthesised
