Medicinal ChemistryLecture 5

SARs and QSARs

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Changing the Existing Substituent of a LeadIs often made with the use of isosteres conceptIsosteres are groups that exhibits some

similarities in their chemical and/or physical properties.

As a result they may exhibit similar pharmacokinetic and pharmacodynamic properties.

I.e. the replacement of a substituent by its isostere is more likely to result in the formation of an analogue with the same type of bioactivity as the lead than the totally random selection of an alternative substituent.

Classical Isosteres and Bioisosteres

Quantitative Structure-Activity Relationships (QSARs)Attempt to remove the element of luck from

drug designEstablishing mathematical relationships in the

form of equations between biological activity and measurable physicochemical parameters.

Parameters represent properties such as lipophilicity, shape and size of drugs.

They are always defined as numbers that are derived from practical data that is related to the property that the parameter represents

It is possible to either measure or calculate these parameters for a large number of compounds and relate their values to the biological activity by means of mathematical equations using statistical methods (e. g regression analysis).

These equations can be used to make informed choices about what drug analogue to synthesize.

Regression AnalysisA group of mathematical methods used to

obtain mathematical equations relating different sets of data that have been obtained from experimental work or calculated using theoretical considerations.

Data are fed into suitable computer program, which on execution, produces an equation that represent the line that is the best fit for those data.

Using statistical data from other compounds, a theoretical value for x parameter for an as yet unsynthesized drug can be calculated.

Substituting this value in the appropriate equation relating activity to the parameter makes it possible to calculate the theoretical activity of the unsynthesized compound.

Alternatively, the equation can be used to determine the value x for the parameter y that would give optimum activity.

As a result only the analogues that will give the value of y at the region of x need to be prepared.

The main properties that affect the activity of the molecule are:

1.Lipoliphicity 2.Electronic Effects within the molecule3.Size and shape of the molecule (steric

effects)

LipophilicityMeasure of the drug solubility in the lipid

membrane

Determines how easily the drug passes through the lipid membrane.

Partition coefficient is the main parameter used to represent lipophilicity

Electronic effectsOf the groups within the molecule will

affects its electronic distribution.

Electronic distribution has a direct bearing on how easily and permanently the drug will bind to the receptor

Hammet ð constant is used to represent electronic effects

Steric EffectsDrug size and shape will determine

whether the drug molecule will be able to get close enough to the target site in order to bind to it.

Are represented by Taft’s Ms steric constants

QSAR EquationsUsually take the form:

In these equations, activity is normally expressed as:

Log [1/(concentration term)], usually C, the minimum concentration required to cause a defined biological response.

When the correlation between the parameter and the activity is not strong, other parameters must be playing an important role and therefore must be incorporated in the QSAR equation.

QSAR studies are normally carried out on a series of structurally similar compounds.

They can also be carried out on diverse set of compounds

In each case, the widest range of parameters must be considered

LipophilicityPartition coefficient is used along with

another parameter (π) to represent lipophilicity.

Partition coefficient is used for the whole molecule while π is related to substituent groups

The nature of the relationship between P and drug activity depends on the range of P values obtained for the drugs used.

If the range is small the results may be expressed as a straight line equation having the formula below in which K1 and K2 are constants:

Over larger ranges of P values the graph of log 1/C against log P often has a parabolic form with a maximum value (log P˚).

The existence of this maximum value implies that there is a balance between aqueous and lipid solubility for maximum biological activity.

Below P˚ the drug will be reluctant to enter the membrane whilst above P˚ the drug will be reluctant to leave the membrane.

Log P˚ represent the optimum partition coefficient for biological activity

Hansch found that these parabolic relationships could be represented reasonably accurately by equations of this form (where K1, K2, and K3 are constants that are normally determined by regression analysis):

Lipophilic Substituent Constants πAlso known as hydrophobic substituent

constantsThey represent the contribution that a group

make to the partition coefficient and were defined by Hansch and his coworkers as :

Where PRH and PRx are the partition coefficients of the standard compound and its monosubstituted analogue respectively.

When many substituents are present, π of the compound is the sum of π values for all the substituents.

The value of π for each substituent will vary with the structural environment of that substituent

This value will also depend on the solvent system used in the determination of the partition coefficient value

Consequently, average values or the values relevant to the type of structure being investigated may be used in the determination of the activity relationship.

Positive π value means that the substituent has a higher lipophilicity than hydrogen and so will probably will increase the concentration of the drug in the organic phase and by inference its concentration in the membrane of the the biological system.

Negative π values means that the substituent has a lower lipophilicity than hydrogen and so will probably increase the concentration of the drug in the aqueous phase and by inference its concentration in the aqueous media of the biological systems

Lipophilic constants are frequently used when dealing with a series of analogues in which only the substituents are different

This usage is based on the assumption that the lipophilic effect of the unchanged part of the structure is similar for each of the analogues.

Next LectureElectronic Parameters

Steric Parameters

Receptors and Receptor Sites

The End