lead optimization.pdf

7/28/2019 lead optimization.pdf

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Lead Optimization

1. Identification of pharmacophore2. Functional group modification

3. Structure-Activity relationship

4. Structure modification to increase potency and therapeutic index

homologation

chain branchingring-chain transformation

bioisosterism

5. Quantitative structure-activity relationships (QSAR)

Physicochemical parameterselectronic effects: Hammett equation

lipophilicity effects: basis for the Hansch equation

steric effects: Taft equation

Correlate parameters to biological activity

Hansch analysisFree and Wilson orde novo method

Topliss analysis

6. Molecular graphics-based drug design


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1. Identification of pharmacophore

Pharmacophore: the relevant groups on a molecule that interact with a receptor andare responsible for the biological activity

----these groups are in direct contact wi th the enzyme or receptor

----keep the pharmacophore chemically and conformationally unchanged,

the other parts of the molecule can be extensively modified without

hurting the biological activity

Structure trim down

Increase complexity/rigidity

1000 times

as potent as morphine


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2. Functional group modification

In some cases, certain functional group wi ll elicit a particular effect.Modif ication of the group may enable or disable certain biological effects

(i. e. side effects).

Chlorothiazide

--antihypertensive agent (good quality)--strong diuretic effect (bad side effects)

Diazoxide

--antihypertensive agent--no diuretic effect


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3. Structure-Activity relationship

There are many structural features for any active compounds.Some of these features are important for the activity and the others are not.

(1) NH2

and sulfonyl (R) should be para

(2) NH2 should be unsubstituted

(3) Benzene ring should not be replaced by other ring systems. No additional substitution

(4) R could be variable

(5) N-monosubstitution (R=SO2NHR) results in potency increase

(6) N-disubstitution (R=SO2NHR) results in inactive compounds

R =


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4. Structure modification to increase potency and therapeutic indexPotency: Kd, Ki, LD50, EC50, etc.

Therapeutic index (ratio): a measure of the ratio of undesirable to desirable drug effectshomologation

chain branching

ring-chain transformation

bioisosterism

A. Homologation:

a homologous series is a group of compounds that differ by a constant unit,

usually CH2


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B. Chain branching

C. Ring-chain transformation

Affects (1) lipophilicity, (2) interaction with the enzyme or receptor. It could increase

or decrease drug potency and therapeutic index

Antimalarial drug

Amine: pr imary > secondary > tertiary

Branching decrease lipophilicity

when lipophilicity is major factor in activity,

Branching generally decreases the potency

X = H, R = CH2CH(CH3)CH2N(CH3)2

Ant ispasmodic and ant ih istamine

Methdilazine

Trimeprazine

Prochlorperazine

Greatly increase the effectsOf preventing nausea and vomitt ing


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D. Bioisosterism

Bioisosteres are substituents or groups that have chemical or physical simi larities,

And which produce broadly similar biological properties.

Bioisosterism is a very successful approach to lead optimization. By making a

bioisosteric replacement, the potency is basically unchanged but many other

parameters of the drug molecule will be changed: size, shape, electronic distribution,

lipid solubil ity, water solubil ity, pKa, chemical reactiv ity, and hydrogen bonding, etc.

It can be used to have the effects of :

a. Structure

b. Receptor interaction

c. Pharmacokinetics

d. Metabol ism


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Before bioisosteric replacement:

Phenothiazine, neuroleptic drugs

After bioisosteric replacement:

Dibenzazepine, antidepressant drugs


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E. Quantitative structure-activity relationships (QSAR-rational drug design)

The concept of quantitative drug design is based on the fact that the biologicalproperties of a compound are a function of its physicochemical parameters.

Physical properties: solubili ty, lipophil icity, electronic effects, ionization,

stereochemistry, etc.

Fundamental physicochemical parameters

electronic effects: Hammett equation

lipophilicity effects: basis for the Hansch equationsteric effects: Taft equation

1. Electronic effects: Hammett equation

How to correlate k and Ka:

Linear free-energy relationship


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: substituent constants, additive: a sensit ivity measure of the reaction to the subst ituents.


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2. Lipophilicity effects: Basis of Hansch equation

is the degree of dissociation of

the compound in water.


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Lipophilicity subst ituent constant, additive

Hammett equation

for derivation


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Factors affecting :Inductive / resonance effect

Involvement of H-bond

Steric effects

Conformational effects

Example


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3. Steric effects:The Taft equation

Es = steric parameter, additive

The relative rates of the acid-catalyzed hydrolysis of alpha-substi tuted acetates

X CH2CO2Me, Es(CH3) = 0

Molar refractivity: another parameter to indicate steric effect

It is defined by the Lorentz-Lorenz equation


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Correlate parameters to biological activityHansch analysis

Free and Wilson orde novo method

Topliss analysis

1. Hansch analysis: a linear multiple regression analysis

C: concentration (or dose)

that elicits a standardbiological response.

S: topography term indicating

The size and shape of the molecular

ASSUMPTIONS:Conformational change ignorable, metabolism doesnt interfere activity

Linear free energy terms relevant to receptor affinity is additive

The potency-lipophilici ty relationship is parabolic or linear.

STRENGTHS: WEAKNESSES:

Simple organic parameters a comprehensive data setQualitative prediction with large number of compounds for analysis

statistic confidence expertise in statistics and computer skills

Easy to use, inexpensive models of small molecule interaction

steric effects in biological systems are different

parameters obtained under non-biological conditions

optimize only a given structural framework

extrapolations lead to false predictions


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2. Free-Wilson orde novo method

A method for the optimization of substituents within a given molecular framework.

Assumption:

Introduction of a particulat substituent at any one posit ion in a molecule always

Changes the relative potency by the same amount, regardless of what other

Substi tuents are present in the molecule

A series of linear equations can be written to assess the occurrence of additive

Substituent effects and quantitatively estimate their magnatude.

BA = magnitude of biological activity

Xi is the ith substituent (=1 if present, =0 if absent)

ai is the contribution of the ith substituent to the BA

is the overall average activi ty of the parent skeleton.

Free SM Jr. Wilson JW, 1964. J. Med. Chem. 7, 395

Blankley CJ, 1983. In Quantitative structure-activity relationships of drugs (Topliss , JG Ed.)

Chap.1. Academic Press, New YorkFujita T, Ban T. 1971, J. Med. Chem. 14, 148


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3. Topliss analysis

A nonmathematical, nonstatistical, and noncomputerized application of Hansch principles.

It is an approach for the efficient optimization of the potency of a lead compound withminimization of the number of compounds needed to be synthesized.

It relies heavily on and values and a much less degree the steric effects.

Only prerequisite for this method is that the lead compound must contain an unfusedBenzene ring. 40-50% drugs are substi tuted benzenes.

Topl iss, JG, 1972. J. Med. Chem. 15, 1006

Topl iss, JG, 1977. J. Med. Chem. 20, 463 4-Cl = 0.71, 4-Cl = 0.23

A result of +, + or bothTry 3,4-dichloro substitut ion

To determine + or + is more importantUse SPh, SPh = 2.32, SPh = 0.18


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6. Molecular graphics-based drug design

This assumes the better the complementary fi t of the drug to the receptor, the more potent

The drug will be. This is the lock-and-key hypothesis of Fischer.

To find a structure match, a computer technology called DOCKING is used.

It is the computer-assisted movement of a terminal-displayed molecule into its receptor.

Kuntz et al. developed a shape-matching algorithm for rigid ligands:Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE 1982, J. Mol. Biol .161, 269

It was modified to be applicable to flexible ligands:DesJarlais RL et al. 1986. J. Med. Chem. 29, 2149

DesJarlais RL et al. 1988. J. Med. Chem. 31, 722

In addition to considering shape-matching, energetic of the docking also accounted:Goodford PJ. 1985. J. Med. Chem. 28, 849

Although few X-ray structures, topography of an unknown receptor could be deduced from

Related known receptor structures:

Carlson GM et al. 1986. J. Theor. Biol. 119, 107Blaney et al. 1982. J. Med. Chem. 25, 785

Also, a technique is available to identify the pharmacophore geometry of an unknown

receptor from data of known ligand binding studies:Marshall GR et al. 1981. Mol. Pharmacol. 19, 307

Marshall GR et al. 1980. Annu. Rep. Med. Chem. 15, 267Marshall GR. 1985. Ann. N. Y. Acad. Sci. 439, 162

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