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STRUCTURE ACTIVITY RELATIONSHIP

Presentation · March 2019

DOI: 10.13140/RG.2.2.24933.45286

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Al-Andalus University for Medical Sciences

Faculty of Pharmacy

STRUCTURE ACTIVITY
RELATIONSHIP

4th Lecture
Dr. Samer Housheh

INTRODUCTION

• Medicinal Chemistry is the science that deals with the design and development of
new pharmaceutical agents.

• Medicinal Chemist interests in:

• The synthesis of drugs.

• The isolation of natural products.

• Establishing the structure activity relationships of the compounds.

• Studying the drug-target interaction.

• The pharmacokinetic profile of drugs

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DRUG DISCOVERY

• Drug discovery is a costly and time consuming process… from 10000 obtained compounds,
only one will reach the market.

• After establishing the safety and efficacy of the designed compound on laboratory animals,
clinical trials must be applied on human.

CLINICAL TRIALS

• Phase-I (lasts for 1 month -1 year): evaluate the safety, tolerability, pharmacokinetic and
pharmacological activity of drugs on 20-100 volunteers.

• Phase-II (lasts for 1-3 years): further assess the efficacy, safety of drugs in addition to dosing
regimen in 300-600 patients.

• Phase-III (last for 2-6 years): covers several thousands of patients in clinics or hospitals; study
the activity and possible side effects on the long term.

• Phase-IV: it is the post marketing feedback, after prescribing drugs to the out patients.

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LEAD COMPOUND

• Is a prototype compound that has many attractive properties, most importantly, good activity, stability and
suitable pharmacokinetics.

• Lead optimization is to modify the chemical structure of the lead compound in order to improve the desired
properties and trying to minimize the unwanted ones.

• Drug candidate and clinical drug

• Drug candidate: is that drug obtained from the lead optimization experiment….needs extensive studies to be
clinically available.

• Clinical drug: compound that is ready for clinical trials.

LEAD DISCOVERY

• Is the first step in drug discovery.

• You can not discover a lead if you do not have:

• A well established bioassay…that will study the efficacy and potency of compounds.

• High throughput screening and ultra high throughput screening.

• Enzymatic assay.

• Instrumental analysis such as MS and NMR to interpret the bioassay results.

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SOURCES OF THE LEAD

1. If the biological target is known, then the lead compound will be the natural ligand of this
receptor or enzyme

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2. The marketed drugs can be used as lead compounds.

3. Random screening: this approach is used if we do not know the biological target:

• Examples:
• The sulfa drug; sulfanilamide was used as the lead for the development of many sulfa
drugs.

• Aminoglycosides and Tetracyclines were discovered after random screening of soil

samples on different bacterial strains

4. Non-random screening: in this approach the tested compounds having some structural
similarity to a weakly active agents.

5. Drug metabolism studies:

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6. From clinical observations: in this case the drug candidate exhibits more than one
pharmacological action:

Examples: (Drugs off Label)

• Sildenafil was designed for anti-hypertensive action but found to improve the erectile
function.

• Buclizine and Meclizine first synthesized as anti-allergic agents, but they exhibited a
good activity in treating motion sickness.

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LEAD MODIFICATION

• The aim here is to improve the desired properties in the lead compound and
try to reduce the toxic or unfavorable effects.

• The first step in this process is to identify the PHARMACOPHORE.

• Pharmacophore is a collection of groups in the molecule that interact with

the receptor or the enzyme and are responsible for activity

PHARMACOPHORE AND
AUXOPHORE

• Auxophore: is the groups rather than the pharmacophore in the chemical

structure.

• Many roles have been identified for the auxophore:

• Hold the pharmacophoric groups in their place.

• Interfere with the binding to the receptor…un-favorable.

• Occupy an inert space.

• Affect the pharmacokinetic properties of the whole structure.

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EXAMPLE OF THE STUDY OF

PHARMACOPHORE

• The pharmacophoric groups in opioid analgesics are shown below (Bold style):

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• The other groups (not in the bold style) are auxophoric group.

LEAD MODIFICATION

• The second step in the lead modification is the functional group modification
depending on the study of the pharmacophore.

• Example: sulfonamide lead modification:

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• The second step in the lead modification is the functional group modification depending on the study of the
pharmacophore.

• Example: sulfonamide lead modification:

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• The third step is to construct the structure activity relationships.

• Drugs can be classified into:

• Structurally specific: here the drug binds to specific site (receptor, enzyme, DNA,…etc).

• Structurally non-specific: drug has no specific site to bind with in order to exert its
pharmacological effect (such as gaseous anesthetics, disinfectants and most of sedative
hypnotics)

• Structurally specific drugs are more potent than structurally non-specific ones

STRUCTURAL MODIFICATION

• The main aim is to get more active, potent and safer agents compared
to the lead compound.

• Methods for structural modification:

1. Homologation: is to lengthen the alkyl chain in the chemical structure by CH 2:

• Chain length up to 9 carbon atom….tolerable (optimum lipophilicity and

water solubility.

• Chain length more than 9 carbon atoms…low water solubility… low

availability.

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STRUCTURAL MODIFICATION

2. Chain branching:
• alkyl branching will lower the lipophilicity.
• Alkyl branching will weaken the binding with the biological target.

STRUCTURAL MODIFICATION

3. Ring chain transformation:

• Affects both lipophilicity and drug metabolism

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STRUCTURAL MODIFICATION

4. Molecular Disconnection /Simplification

STRUCTURAL MODIFICATION
5. BIOISOSTERISM

• Bioisosteres are groups or substituents that have chemical or physical similarities which produce
similar biological activity.

• Importance of the use of Bioisosteres:

• Alter the pharmacokinetic properties.

• Decrease toxicity.

• Modify activity.

• Potentiate activity.

• Two types of Bioisosteres:

• Classical Bioisosteres.

• Non-classical Bioisosteres.

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CLASSICAL BIOISOSTERES

• Are atoms or molecules in which the peripheral layers of electrons can be

considered identical.

• Subclasses:

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NON-CLASSICAL BIOISOSTERE

• They do not have the same no. of atoms…this means that the size, shape and
electronic properties are different…at the same time they have the same impact
on biological activity.

• Examples:

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STRUCTURAL MODIFICATION TO
IMPROVE ORAL BIOAVAILABILITY

• Factors affecting oral bioavailability:

• Physicochemical stability.

• Biological stability:

• Effect of intestinal enzymes.

• First pass metabolism.

• Lipophilicity.

• Extent of ionization.

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LIPOPHILICITY

• The orally administered drug must have moderate lipophilicity (logP = 2-5) in order
to absorbed through the lipophilic mucus membrane.

• It is recommended that one can predict the lipophilicity of the chemical compound
before start synthesizing it.

• P = [C]octanol /[C]water
• Octanol was selected because it simulates the lipophilic membrane; lipophilic and sparingly
soluble in water

• Ionized drug will have lower lipophilicity than the neutral form.

• α is the degree of dissociation in water, depends on the ionization constant.

• LogD: is the log of distribution coefficient that describe the
lipophilicity of ionizable compound

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• Example of logD

PREDICTION OF LIPOPHILICITY

• To predict the lipophilicity, we must know the lipophilicity of substituents.

• Lipophilicity substituent constant (π)

•
• π = logPX –LogPH (Hansh approach)

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SUBSTITUENT OR FRAGMENT
CONSTANT

Example
•Calculate the logP of Aspirin:

•logP = 1.67 - 0.03 - 0.56 + 0.89 = 1.97

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Calculate the approximate LogP for the following drugs using the Hansh equation and fragment table

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OTHER FACTORS AFFECTING

LIPOPHILICITY

• Branching: logP will be lowered by 0.2 per branch.

• Inductive effect of electron withdrawing groups.

• Resonance effect: if it will affect the possibility of H-bonding.

• Example

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EFFECT OF IONIZATION

• Extent of ionization of drugs may affect the following:

• Lipophilicity.

• Oral availability.

• Receptor-drug interaction.

• Excretion.

• Distribution

• At a given pH, there is an equilibrium between the ionized and unionized form.

• Only the unionized form will be absorbed from the GIT.

• The equilibrium between the ionized and unionized will be reestablished to generate unionized drug again for absorption

(what are the factors affecting this equilibrium?)

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Example

Electron Withdrawing effect of sulfonate Electron donating effect of alkyl chain

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Example

LIPINSKI’S RULE OF FIVE

• The orally administered drug must not have:

• A molecular weight > 500 Dalton
• LogP > 5
• H-bond donor > 5
• H-bond acceptor > 10
• There are some exceptions out of this rule:
• Drugs that have specific transporters such as peptidomimetic agents.
• Drugs targeting CNS should have:
• H-bond donor ≤ 3
• H-bond acceptor ≤ 6

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VEBER FINDINGS

• For better oral availability, drug candidate must have:

• Rotatable bonds ≤ 10

• Polar surface area ≤ 140 A°2

• Total hydrogen bond count ≤ 12

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AJAY FINDINGS

• For drugs targeting CNS:

• If the molecular weight, the degree of branching, the no. of rotatable bonds
or the no. of H-bond acceptors increased, the compound will less likely to
be CNS active.

• If the aromatic density, no. of H-bond donors or logP is increased, the

compound is more likely to be CNS active.

Some Exceptions

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THANKS

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