Amides in Drug Design and Binding Interactions

Drug Design: Optimizing Target Interactions

• A lead compound, once discovered, serves as the starting point for drug design.
• Various properties are considered during drug design.
• The eventual drug should have high selectivity and activity for its target.
• It should have minimal side effects.
• The drug should be chemically stable and synthesized easily.
• It should be non-toxic and have tolerable pharmacokinetic properties.
• Pharmacodynamic and pharmacokinetic properties are optimized together during drug development.
• It is unwise to invest time in perfecting a drug's interaction with its target if it cannot reach the target due to adverse pharmacokinetic properties.

Structure-Activity Relationships (SAR)

• After lead compound structure determination, medicinal chemists analyze structure-activity relationships.
• The goal is to identify parts of the molecule crucial for biological activity and those that are not.
• X-ray crystallography, if the compound can be crystallized in complex with the target, can help solve the crystal structure of the complex.
• Modeling software helps identify key binding interactions.
• If the target structure is unknown or cannot be crystallized, traditional methods involve synthesizing analogues of the lead compound.
• Recognizing functional groups and their potential intermolecular interactions with the target is crucial.

Binding Role of Alcohols and Phenols

• Alcohol and phenol groups are common in drug molecules and frequently involved in hydrogen bond formation.
• Hydrogen is a hydrogen bond donor (HBD), while oxygen acts as a hydrogen bond acceptor (HBA).
• Presence of hydrogen bond interactions may be important for drug binding.
• Analogy synthesis, like methyl ether and ester, is useful to evaluate the importance of hydrogen bonding, since it can disrupt hydrogen bonding.
• Removing the hydrogen atom from the hydroxyl group (or phenol) breaks hydrogen bonds.

Binding Role of Aromatic Rings and Alkenes

• Aromatic rings and alkenes are planar and hydrophobic.
• They interact with the hydrophobic regions of the binding site through van der Waals forces.
• Analogy synthesis using saturated analogues is helpful in testing for the role of this alkyl region.
• Cyclohexane's axial protons create a buffer space, potentially hindering binding.
• Saturated alkyl analogues are generally easier to synthesize than aromatic ring analogues.

Binding Role of Ketones and Aldehydes

• Ketone groups are planar and can form two hydrogen bonds using their two lone pairs of electrons on the oxygen atom of the carbonyl.
• They can interact with binding sites through dipole-dipole interactions due to the significant dipole moment.
• Ketones can be reduced easily to alcohols, which is a common method for investigation.
• Reducing a ketone to an alcohol changes its geometry from planar to tetrahedral.
• This modification affects hydrogen bonding and dipole-dipole interactions, often weakening them.

Binding Role of Amines

• Amines are important functional groups in many drug designs.
• Involved in hydrogen bonding as a hydrogen bond donor/acceptor.
• Protonation during target binding converts amines to ions, preventing them from accepting hydrogen bonds; however, they can still function as hydrogen bond donors.
• Strong ionic interactions with carboxylate ions in the binding site are also possible.
• Amide analogues can be used to assess the role of ionic or hydrogen bonding interactions.
• Tertiary amines are harder to convert to amides than secondary amines.
• The secondary amide can still act as a hydrogen bond donor, however the steric hindrance from the acyl group may diminish it.

Binding Role of Amides

• Many drug compounds are peptides or polypeptides with amide bonds.
• Amides likely interact with binding sites through hydrogen bonding.
• The carbonyl oxygen acts as a hydrogen bond acceptor.
• Nitrogen atoms cannot function as hydrogen bond acceptors as their lone pairs are involved in bonding with the carbonyl group.
• Primary and secondary amides can act as hydrogen bond donors.
• Secondary amides are the most prevalent type in peptide lead compounds.

Binding Role of Quaternary Ammonium Salts

• Quaternary ammonium salts are ionized and interact with carboxylate groups through ionic interactions.
• An induced dipole interaction can occur between the quaternary ammonium ion and any aromatic rings.
• This is a pi-cation interaction.
• Analogy synthesis using tertiary amine as replacement can be used to assess the importance of the interactions.
• Conversion of the amine to an amide will prevent ionization and the possibility of the interaction.

Binding Role of Carboxylic Acids

• Carboxylic acids are often found in drug molecules.
• They can act as hydrogen bond acceptors or donors, or as carboxylate ions.
• Carboxylate ions act as hydrogen bond acceptors.
• They can also act as ligands for metal ion cofactors, like zinc, in various enzymes.
• Analogies, like esters, primary alcohols, primary amides, and ketones, are synthesized and tested to evaluate the contribution of carboxylic acids to binding.

Binding Role of Esters

• Ester groups can interact with binding sites as hydrogen bond acceptors.
• Carbonyls are more likely than alkoxys to act as hydrogen bond acceptors.
• Esters undergo hydrolysis in vivo by esterases, potentially shortening the drug's lifetime.
• Electronic effects can stabilize ester groups and protect them from metabolism.
• Ester groups can sometimes be used as a way to mask polar functional groups.
• In these cases, this is known as a prodrug strategy

Binding Role of Alkyl and Aryl Halides

• Alkyl halides (chlorine, bromine, or iodine) are reactive due to the halide ion as a good leaving group.
• They tend to react with nucleophilic groups, potentially leading to problems.
• Alkylation reactions with this halide may result in the drug permanently binding to other macromolecules.
• Alkyl Fluorides are not reactive due to stronger C-F bonds.
• Fluorine-substitution can be a way to probe for the role of the molecule

Binding Role of Thiols and Ethers

• Thiol group (S-H) is a good ligand for d-block metal ions; it is used for inhibiting enzymes containing zinc.
• Analogy synthesis with the alcohol can be used to assess the importance of interactions with d-block metal ions.
• Ether's oxygen atom can act as a hydrogen bond acceptor, though it is often a poor acceptor in aromatic ethers.
• Replacing the oxygen atom with a methylene group typically decreases binding affinity.

Binding Role of Other Functional Groups

• Functional groups may influence electronic properties, molecular shape, or act as metabolic blockers.

Binding Role of Alkyl Groups and Carbon Skeleton

• Alkyl groups are hydrophobic and interact with hydrophobic binding pockets through van der Waals.
• Analysis of analogue synthesis is a good process to assess the role of alkyl group in binding.
• The removal or variation in the structure of alkyl groups can be investigated through synthesis and analysis.

Binding Role of Heterocycles

• Heterocycles are cyclic structures with one or more heteroatoms (e.g. oxygen, nitrogen, sulfur).
• They often have diverse bonding forces that can lead to interactions with the binding site.
• Planar groups like heterocycles have an important directional aspect for hydrogen bonding.
• The exact position and orientation of the heterocycle in the binding site determine binding success and interaction strength.
• Studying tautomers can deepen our understanding of how drugs interact with their binding sites.

Isosteres

• Isosteres are atoms or groups sharing the same valency and similar chemical or physical properties.
• They can be used to assess the importance of a specific group in binding.
• For example, replacing O with CH2 does not affect the size but can influence polarity, electronic distribution, and bonding.

Extension of Structure

• Extending a structure adds another functional group or substituent to probe for additional binding interactions with the target molecule.
• Lead compounds have functional groups to interact with some of the important binding regions.
• Often, compounds will not interact with all the binding sites and can fail to bind to a specific binding region.
• Chain, Ring, and Ring fusion tactics may lead to structural variations that will provide insights.
• These could be useful for enhanced hydrophobic, hydrogen, and/or ionic interactions.

Ring Variations

• Replacing the original ring with a range of other heteroaromatic rings of different sizes and positions can be a useful strategy.
• Examining the relationship between ring size and activity can determine the optimal ring configuration.

Ring Fusions

• Extending a ring by fusing it with another ring can sometimes increase interactions and selectivity.

Isosteres and Bioisosteres

• Isosteres and bioisosteres are important in varying the characteristics of the molecule in a relevant way, while keeping polarity, electronic distribution, and bonding.
• These modifications can be for increasing size or electronic property importance.
• They can help determine the importance of size effects and electronic factors on drug activity.
• Bioisosteres are particularly valuable in modifying groups with unfavourable properties (e.g. toxicity)

Simplification of the Structure

• Simplification is a strategy for reducing the complexity of lead compounds.
• The essential groups identified through SAR are the focus of the structure, while eliminating non-essential elements.
• In this way, groups are removed that are not a part of the pharmacophore and the carbon skeleton.
• This strategy is usually progressed in steps.
• Removing asymmetric centers are also useful

Rigidification of the Structure

• Increasing drug rigidity can improve pharmacological aspects such as activity or reduce side effects.
• Molecules with flexible components may interact with different binding regions of a receptor or enzyme, causing undesired effects.
• Rigidification helps restrict conformations to only active ones, which then increases activity.
• Rigidification is also possible through intramolecular hydrogen bonding.

Conformational Blockers

• Conformational blockers can also restrict the number of possible conformations.
• In certain cases, a simple substituent can hinder free rotation of a single bond and lead to a high decrease in activity.

Structure-Based Drug Design

• Knowledge of the target structure leads to a more focused drug design process, rather than using experimental results alone.
• X-ray crystallography is crucial to visualize target structure in detail.
• Molecular modeling assists in testing and adjusting drug structures for optimal fit in the active binding site.

Elements of Luck and Inspiration

• Drug discovery often combines rational design, trial and error, hard work, and serendipity.
• Reading literature about analogous compounds frequently helps scientists identify potential modifications to enhance drug activity

Chiral Drug Simplification

• Separating enantiomers of drugs is critical to assess their activity on specific receptors and minimize adverse reactions.
• Synthetic strategies are beneficial in simplifying drugs by eliminating asymmetric centers.

Other Principles & Strategies

• Alkyl and aromatic substituents are often varied to fine-tune binding interactions; selection of appropriate substituents is dependent on the nature of the binding site

Explore the role of amides in drug design, focusing on their interactions with binding sites and hydrogen bonding characteristics. This quiz will challenge your understanding of amide functionality, the significance of their planar nature, and their influence on the activity of drug compounds. Test your knowledge on the impact of structural modifications and the properties of various functional groups in pharmaceutical applications.