Drug Design and Medicinal Chemistry Concepts

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Questions and Answers

What is the optimum chain length for N-Phenethylmorphine to ensure effective binding?

2 (correct)

What is the primary rationale for ring expansion in drug design?

To increase the size of the compound

To improve stability

To improve overlap of binding groups with their binding regions (correct)

To increase toxicity

What type of regions are targeted when considering ring expansion and contraction?

Polar regions

Ionic regions

Hydrophobic regions (correct)

Aromatic regions

How does ring variation contribute to drug efficacy?

By improving selectivity against specific targets Signup and view all the answers

In the context of medicinal chemistry, why is N-Phenethylmorphine significant?

It illustrates the importance of chain length in binding efficacy. Signup and view all the answers

What is one advantage of simplifying lead compounds from natural sources?

It can increase selectivity and reduce toxicity. Signup and view all the answers

What is a potential disadvantage of oversimplifying a medicinal compound?

Higher likelihood of interacting with multiple targets. Signup and view all the answers

Rigidification of lead compounds is often pursued because:

It improves the binding at a single target site. Signup and view all the answers

Which of the following techniques is NOT suggested for simplifying lead compounds?

Add extra functional groups. Signup and view all the answers

What is an example of a CCK antagonist mentioned in the content?

Asperlicin Signup and view all the answers

What is one primary goal of optimizing drug binding interactions?

Increase activity and reduce dose levels Signup and view all the answers

Which strategy can be used to potentially improve the binding of a drug by altering its structure?

Varying aryl substituents Signup and view all the answers

In the context of drug design, what does the term 'isosteres' refer to?

Compounds with similar physical properties but different structures Signup and view all the answers

How does varying the length and bulk of alkyl substituents affect drug binding?

It optimizes interactions with hydrophobic regions in the binding site. Signup and view all the answers

What is the significance of lipophilicity in drug activity?

It can enhance the antimicrobial activity of the drug. Signup and view all the answers

What is the primary reason why amides and amidines do not fit the same steric and electronic rules?

They have differing atomic compositions. Signup and view all the answers

What concept did Friedman introduce to define isosteres with similar biological activity?

Bioisostere Signup and view all the answers

Which of the following is the least disturbing replacement when adding deuterium to a compound?

Replacing hydrogen with deuterium. Signup and view all the answers

What effect does deuterium have compared to hydrogen in a compound?

Increases metabolic stability. Signup and view all the answers

What proportion of all drugs are fluorinated compounds?

20% Signup and view all the answers

What is a primary advantage of introducing rigid structures in drug molecules?

Increases selectivity for desired conformations Signup and view all the answers

Which method is NOT used to introduce rigidity in molecules?

Adding flexible side chains Signup and view all the answers

What is one consequence of using isosteric replacement in drug design?

It can lead to similar, opposite, or different biological activity. Signup and view all the answers

How can introducing a methyl group act as a steric blocker in drug design?

It retains the active conformation while inducing steric clash. Signup and view all the answers

Which of the following best describes a disadvantage of rigidifying a drug molecule?

It complicates the synthesis of the drug. Signup and view all the answers

What effect does coplanarity have in drug design with respect to steric blockers?

It allows for better conformational control in the active site. Signup and view all the answers

Which of the following is a commonly encountered isostere?

–O– Signup and view all the answers

Which of the following statements about conformational restraint is true?

It increases the activity by favoring the active conformation. Signup and view all the answers

What effect does fluorine substitution have on the basicity of adjacent nitrogen centers?

It decreases the basicity of adjacent nitrogen centers. Signup and view all the answers

Which compound has the highest pKa value among those listed?

(±) -1 Signup and view all the answers

What is the pKa value of compound (+) -2?

4.5 Signup and view all the answers

Which of the following compounds contains two fluorine substitutions?

(+) -9 Signup and view all the answers

What structural modification is present in compound (+) -4 compared to compound (+) -3?

Substitution of R5 with a fluorine atom. Signup and view all the answers

What is the role of the 'Oxyanion hole' as depicted?

To stabilize negative charges on species. Signup and view all the answers

Which compound has a pKa closest to neutral conditions?

(±) -1 Signup and view all the answers

What notable feature is present at the P pocket according to the structure?

Presence of a nitrogen atom. Signup and view all the answers

How does the substitution on R5 in compound (+) -6 affect its properties?

It introduces a more polar environment. Signup and view all the answers

What is the primary role of the amino acids Asn98 and Ser195 in the depicted structure?

Formation of hydrogen bonds. Signup and view all the answers

Study Notes

Optimizing Drug Binding Affinity

Drug design aims to increase activity and reduce dose levels, while also increasing selectivity and reducing side effects.
Strategies include varying alkyl, aryl substituents, chain extensions/contractions, ring expansions/contractions, ring variations, isosteres, simplification, and rigidification.

Vary Alkyl Substituents

Alkyl groups in a lead compound can interact with hydrophobic pockets in a binding site.
Varying the length and bulk of the alkyl group optimizes the interaction.
Increasing selectivity is possible by altering alkyl groups. Specific examples include adrenaline, noradrenaline, salbutamol (Ventolin), and propranolol.
Lipophilicity (log P) is a key factor, affecting antimicrobial activity. A graph shows a log P distribution curve.

Chain Extension/Contraction

Chain extensions or contractions alter the length of a molecule's binding region affecting binding strength.
An example is N-phenethylmorphine where the optimum chain length is 2.

Ring Expansion/Contraction

Improving the overlap of binding groups with their binding regions is the rationale behind ring expansion and contraction.
Example: Cilazaprilat.

Ring Variations

Ring variation improves selectivity, shown by the example of an antifungal agent (structure I) into UK-46245.
Nevirapine (antiviral agent) is another example of improving selectivity through ring variation with a lead compound.

Extension - Extra Functional Groups

Adding extra functional groups to a drug can improve its interactions with the receptor.
An example is ACE inhibitors.

Simplification

Lead compounds from natural sources are often complex, making synthesis of analogues difficult, time-consuming, and expensive.
Simplifying the molecule makes synthesis and creating analogues easier, quicker, and cheaper. This may improve binding and reduce toxicity issues by removing excess functional groups.

Remove excess rings / Asymmetric centers

Removing excess rings in medicinal compounds like morphine can lead to compounds like levorphanol and metazocine.
Removing asymmetric centers from a chiral drug creates an achiral drug, often with improved properties.

Example

Asperlicin (CKK antagonist), a possible lead for treating panic attacks could be simplified into simpler molecules like devazepide.
The disadvantages of simplification include potentially decreased activity and selectivity, and increased likelihood of interacting with more than one target binding site.

Rigidification

Endogenous lead compounds which are flexible can sometimes fit several targets due to different conformations (e.g., adrenergic receptor types and subtypes).
Rigidification limits conformations, increasing target selectivity and possibly activity by providing more opportunities for the desired conformation.
Methods use rings, rigid functional groups, or steric blockers to reduce flexibility.

Methods - Introduce rings

Bonds within ring systems prevent rotations.
Introducing rings can rigidify molecules and improve activity and/or selectivity.
An example using this method is Combretastatin.

Methods - Steric Blockers

Introducing steric blocks can prevent unfavourable conformations.
This can improve selectivity by only enabling desirable conformations to bind.
A resulting compound (Example: serotonin antagonist) can subsequently have an increase in activity with a retained active conformation.

Isosterism in Drugs

Isosteric replacement is often used by pharmaceutical companies to modify molecules to improve or alter their biological activity.
There are no universal rules, so the results from isoesters can be similar, opposite, or different to what was expected.
Common examples include substituting sulfur for oxygen, nitrogen for carbon, and changing the number of carbons in a chain.

Isosteres and Bio-isosteres

Isosteres replace a functional group with a group of the same valency (e.g., OH replaced by SH). They potentially improve binding or stability by changing the steric or electronic properties.
Bioisosteres replace a functional group with another that preserves the same biological activity, though not necessarily the same valency.
Using iso/bio-isosteres, a drug candidate may improve potency and selectivity, or have changed lipophilicity and changed/eliminated toxic metabolites.

Why making isosteres/bioisosteres?

Improve potency and selectivity of the drug candidate.
Changing lipophilicity/hydrophilicity
Reduce or eliminate toxic metabolites.

Classical Isotere Groups and Atoms

These describe groups and/or atoms that are considered to be isoelectronic, and so are useful to swap in during drug design.

Non-Classical Isosteres

These are functional groups that do not fit the structural criteria of classical isosterism, but can still be used as bioisosteres to preserve activity and are used in drug design.
Examples given are amide groups, carboxylic acid groups, ester groups, and hydroxyl groups.

Replacement of H by 2H

Replacing hydrogen atoms (H) by deuterium (2H) atoms can lead to compounds with altered physical properties, including increased metabolic stability with less disruption.

Halogens (Fluorine) in Pharmaceutical Products

Fluorine substitution in drugs is common. It affects properties like metabolic stability.
20% of drugs now contain fluorine.
Fluorination reagents are used to incorporate fluorine.

Properties of Fluor in Organic Molecules

Fluorine enhances metabolic stability by reducing cytochrome P450 enzymatic oxidation susceptibility of neighboring moieties.
Fluorine-carbon (F-C) bonds are very stable, helping with drug stability.
Fluorine can serve as bioisosteres (substituting other functional groups).
Substituting hydrogen (H) with fluorine (F) can significantly alter a molecule's conformational preferences, basicity, and lipophilicity.

Van der Waals radius/Bond Lengths/Volumes

These values are useful for comparing substituents based on their size and shape, including whether or not they'll interact favorably with the target protein.

Fluor is not a good H-bond acceptor

Fluorine is not easily polarizable, so it's generally not a good hydrogen bond acceptor.

Introduction of Fluor may dramatically alter the binding mode

The introduction of fluorine atoms in drugs can significantly affect how the drug interacts (binds) with the target (molecule) in a binding site.

Metabolic stabilization / Destabilization

Introducing fluorine atoms can improve metabolic stability, preventing metabolic degradation.
Removing fluorine atoms can decrease metabolic stability, increasing metabolic degradation and potentially hindering drug activity.

Fluor substitution alters the basicity of adjacent N centers

The introduction of fluorine can affect the acidity of nearby atoms within the molecule, most notably Nitrogen atoms.

Improving water-solubility

Increasing the water solubility of a drug can improve its bioavailability and effectiveness.

Methods - Improving Bioavailability

Increasing bioavailability is a key concept to understand in drug design. Methods can be used to enhance absorption, metabolism and excretion pathways, thereby targeting improved drug activity.

Increasing Membrane Permeability

Methods exist to improve the passage of drugs across cell membranes as part of bioavailability, which includes structural modifications such as removing or replacing functional groups (such as carboxyl groups).

Bioisosteres of the peptide bond

Naturally occurring bioisosteres

Natural analogues/isosteres may exist, such as muscimol and glutamate.
Using natural compounds as models for isosteric replacement can leverage known bioactive compounds to guide drug development.

Examples

Examples are provided to show how drugs can be designed to have similar activity to a lead compound.
The processes are shown that can be used to refine the activity and properties of a lead drug candidate.

Making Analogues

Making analogues allows modification of the drug lead candidate to alter its structure, which can be used to alter activity, selectivity, and other properties, including reducing toxicity.

Common sidechain replacements

Commonly used alterations/replacements of side chains to improve or maintain beneficial functionalities in the drug lead.

Sidechain modifications resulting in increased solubility

Improving drug solubility is often a key factor in developing drugs for clinical administration. Methods to alter solubility include making side chain modifications.

Quantitative Structure-Activity Relationships (QSAR)

QSAR relates physicochemical properties to bioactivity.
It attempts to quantify which properties are important for activity and provides predictions about what molecules with similar patterns of properties may also exhibit similar activity.
QSAR equations can involve various factors including log P, electronic (σ, Hammett) and steric (Es, Taft) factors.
Altering the structures and testing them for activity can refine QSAR equations.

Hansch Equation, and example relating potency to partition coefficient, P

The Hansch equation is a commonly used QSAR equation for relating physicochemical properties to biological activity.
It often features parabolic relationships between potency and the partition coefficient (log P) for optimal drug penetration into targets.
The optimal partition coefficient (log P) for drug penetration may vary for different targets, e.g. the central nervous system (CNS), based on the blood-brain barrier.

Hydrophobicity: π vs P

P measures the overall hydrophobicity of the drug, reflecting its transportability in membranes, including the blood-brain barrier.
π measures the local hydrophobicity of a specific area of the drug relative to hydrogen, which can be significant if the drug is directly interacting with a target for its activities.
Substituent hydrophobicity constant (π) allows calculation of the hydrophobic contribution of particular substituents to the overall hydrophobicity of a drug molecule.
The method compares standard compounds with and without substituent (x).

Hydrophobicity of Substituents – the substituent hydrophobicity constant (π)

Tabulated π values exist for various substituents, including aliphatic and aromatic ones.
These are experimentally derived, determined through measuring log P values for the substituted and parent compounds.

π values for various substituents on aromatic rings

π values aid in understanding the contribution of various substituents to the overall hydrophobicity of a compound, most often for aromatic rings.

Electronic Effects: The Hammett Constant σ

The Hammett constant (σ) measures electronic effects (electronegativity and electron donating/withdrawing) of substituents, mainly on aromatic rings.
σ values help relate the substituents' electronic character to changes in reaction rate/equilibrium.
It helps to understand if the groups are electron-withdrawing or electron-donating.

Steric Effects

Steric effects are interactions between different parts of a molecule, or different molecules, due to their spatial orientation (shape).
Steric hindrance can refer to the presence of a bulky group on a molecule which sterically obstructs the molecule from getting into a suitable conformation to bind.
Difficult to quantify.
Taft’s steric factor (Es), molar refractivity (MR), or the Verloop steric parameter are measures/methods that quantify these factors.

Steric Factors: Taft's Steric Factor (Es)

Taft's steric factor evaluates the steric effects on reaction rates for substituted aliphatic esters, especially with regards to the transition state.
Limitations include only applying to specific reaction types and possibly undervaluing the steric effects of groups on intermolecular processes within larger systems.

Steric Factors: Molar Refractivity (MR)

Calculates the molar refractivity (MR) of a molecule using the molecule's volume and polarizability.

Steric Factors: Verloop Steric Parameter

Calculated based on bond angles and van der Waals radii. Used in computer modelling.

3D-QSAR

Physical properties evaluated as a whole instead of individual substituents.
Calculations use advanced modelling techniques.
Advantages include fewer assumptions, broader applicability to various structures.

X-ray crystallography

Used to analyze the spatial arrangement (binding mode) of a drug/enzyme complex.

Pharmacophores

Pharmacophores define the essential groups and their relative spatial arrangements that are crucial for a drug to bind to a target successfully.

Structural (2D) Pharmacophore

Defines minimum skeleton that connects binding groups in a drug.

3D Pharmacophore

Specifies the locations and spatial arrangements of key groups (e.g. hydrogen-bonds, hydrophobic interactions) in space.

The Active Conformation

Identification of the specific three-dimensional arrangement (conformational shape) that drug molecules adopt to interact with the target molecule.
Requires conformational analysis- often difficult for flexible molecules with many possible conformations.
Comparing activity of rigid analogues can help determine the importance of different arrangements and/or interactions in the mechanism.

Pseudoreceptor models

Used to model the environment around a target binding site, which provides a useful surrogate to 3D structures to aid drug design prediction.
Used to explore key ligand-receptor interaction sites, evaluate new candidate compounds, estimate interaction energies, discern the protein folding interaction and energy minimization of ligands to derive their active conformation. This helps medicinal chemists design novel compounds.

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Description

Explore key concepts in drug design and medicinal chemistry through this quiz. Topics include N-Phenethylmorphine, ring expansion, simplifying lead compounds, and strategies for optimizing drug binding interactions. Test your knowledge and understanding of current medicinal chemistry principles.