Drug Design and Medicinal Chemistry Concepts

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.