Drugs and types of bonding (what happens at the target binding site)

sophietevans
Flashcards by sophietevans, updated more than 1 year ago
sophietevans
Created by sophietevans almost 7 years ago
62
2

Description

From the 23-09-13 Medicinal Chemistry lecture.

Resource summary

Question Answer
What is the approach and binding of a drug to its target broadly dependent on? Intermolecular bonding and physicochemical properties.
If a drug reacts with a binding site and becomes permanently attached, what type of intermolecular bond has been formed? A covalent bond.
What is the bond strength range of a covalent bond? 200-400kJ mol^-1
List the types of temporary intermolecular forces that can form between drugs and their targets? These include electrostatic or ionic bonds, van der Waals interactions, dipole-dipole interactions, and hydrophobic interactions.
If intermolecular forces such as dipole-dipole interactions are temporary, why don't molecules fall apart and dissociate? Because their molecular skeletons are bonded together via covalent bonds, which are permanent, high energy bonds. The weaker, temporary interactions can exist within a molecule (intramolecular forces), such as the hydrogen bonding forming tertiary protein structures.
If temporary interactions are possible between the drug and its target, what exists between the unbound and bound drug? An equilibrium. The binding forces are strong enough to hold the drug for a certain period of time to let it have an effect on the target, but weak enough to allow the drug to depart once it has done its job.
What factors determine the length of time that a drug remains at its target? The length of time the drug remains at its target depends on the number of intermolecular bonds involved in holding it there. Drugs that have a larger number of interactions are likely to remain bound longer than those that have only a few. The relative strength of the different intermolecular binding forces is also an important factor. Functional groups present in the drug can be important in forming intermolecular bonds with the target binding site. If they do so, they are called 'binding groups'. However, the carbon skeleton of the drug also plays an important role in binding the drug to its target through van der Waals interactions.
What is pharmacodynamics? The study of how drugs interact with their targets through binding interactions and produce a pharmacological effect is known as pharmacodynamics.
What is the strongest of the intermolecular bonds? Ionic/electrostatic bonds - 20-40 kJ mol^-1.
What is required of the two molecules between which an ionic/electrostatic bond forms? Opposite charges.
With regard to electrostatic/ionic bonds: the strength of the interaction is inversely proportional to... ...the distance between the two charged atoms.
How does the nature of the environment in which the drug-target interaction is occurring affect ionic/electrostatic bonds? The strength of interaction is also dependent on the nature of the environment, being stronger in hydrophobic environments that in polar ones. Usually the binding sites of macromolecules are more hydrophobic in nature than the surface (due to the carbon skeleton of the macromolecule) and so this enhances the effect of an ionic interaction.
The drop-off in ionic bonding strength with separation is less than in other intermolecular interactions. What does this mean for the order in which drug-target interactions occur? If an ionic reaction is possible, it is likely to be the most important initial interaction as the drug enters the binding site.
What is the strength range of hydrogen bonds? What does the strength of the bond formed depend on? A hydrogen bond can vary substantially in strength (from 16-60kJ mol-1, depending on how strong the hydrogen bond acceptor and hydrogen bond donor are.
In a pair of atoms that are hydrogen bonded, which is the hydrogen bond donor? The hydrogen bond donor is usually the electronegative atom that the hydrogen is bound to, which has a greater attraction for electrons and so the electron distribution in the covalent bond is weighted towards the more electronegative atom and so the hydrogen gains its slight positive charge.
In a pair of atoms that are hydrogen bonded, which is the hydrogen bond acceptor? The functional group that provides the electron-rich atom to receive the hydrogen bond is the hydrogen bond acceptor. Some groups can act as both, e.g. OH, NH2, and might bind to one ligand as a donor and another as an acceptor - hydrogen bond flip-flop.
So the hydrogen bond donor is usually the electronegative (δ-) atom that hydrogen is covalently bound to - here, this is the O atom of the water molecule. The hydrogen bond acceptor is the electronegative atom that receives the hydrogen bond - it is electron rich (δ-) and hence accepts the electrodeficient hydrogen (δ+).
If we consider the hydrogen bond donor, the hydrogen atom itself, and the hydrogen bond acceptor to be 'X, Y, and Z', what is the ideal angle between these three components to form the strongest hydrogen bonds? • The optimum orientation is where the angle formed between X, H, and Y is 180°. However, the angle can vary between 130° and 180° for moderately strong hydrogen bonds, and can be as low as 90° for weak hydrogen bonds.
Which are the two most common atoms involved as hydrogen bond acceptors in biological systems? N and O. Nitrogen has one lone pair of electrons and can act as an acceptor for one hydrogen bond; oxygen has two lone pairs of electrons and can act as an acceptor for two hydrogen bonds.
Several drugs and macromolecular targets contain a sulphur atom, which is also electronegative. Why is sulphur a weak hydrogen bond acceptor? Because its lone pairs are in third-shell orbitals that are larger and more diffuse - this means that the orbitals concerned interact less efficiently with the small 1s orbitals of hydrogen atoms.
Fluorine is present in several drugs but despite being more electronegative than oxygen or nitrogen and having three lone pairs of electrons, it is a weak hydrogen bond acceptor. Why? Possibly because the fluorine is so electronegative that it clings on to its lone pairs of electrons , making them incapable of hydrogen bond interactions - unlike fluoride ions, which are very strong hydrogen bond acceptors.
What determines the strength of a hydrogen bond acceptor? • Any feature that affects the electron density of the hydrogen bond acceptor is likely to affect its ability to act as a hydrogen bond acceptor: the greater the electron density of the heteroatom, the greater its strength as a hydrogen bond acceptor.
List some hydrogen bond accepting groups commonly present in drugs and binding sites as neutral functional groups. Ethers, alcohols, phenols, amides, amines, and ketones. These groups will form moderately strong hydrogen bonds.
It has been proposed that the pi (π) systems present in alkynes and aromatic rings are regions of high electron density and can act as hydrogen bond acceptors. Why might they be weak hydrogen bond acceptors? The electron density in these systems is diffuse and so the hydrogen bonding interaction is much weaker than those involving oxygen or nitrogen. As a result, aromatic rings and alkynes are only likely to be significant hydrogen bond acceptors if they interact with a strong hydrogen bond donor, such as alkylammonium ion (NHR3+).
What is the bond strength of van der Waals interactions? 2-4kJ mol^-1 - relatively weak
What aspects of molecules do van der Waals forces involve interactions between? Between hydrophobic regions of different molecules, such as aliphatic substituents or the carbon skeleton. The electronic distribution in neutral non-polar regions is never totally even or symmetrical and there are always transient areas of high and low electron densities leading to temporary dipoles. The dipoles in one molecule can induce dipoles in a neighbouring molecule, leading to weak interactions between the two molecules. The strength of this interaction decreases with distance between the two molecules and so the drug has to be close to the target binding site before the interactions become important. However, there may be many of these interactions between a drug and its target and so the overall contribution of van der Waals interactions is often crucial to binding.
Which physicochemical property of atoms between molecules results in the formation of permanent dipole-dipole interactions? Permanent dipole moments result from different electronegativities of atoms and functional groups present in a molecule e.g. the carbon and oxygen in the carbonyl bond of a ketone have different electronegativities.
What role do permanent dipole-dipole interactions play in the binding of a drug to its target? It is possible for the dipole moments of the drug and the binding site to interact as a drug approaches, aligning the drug such that the dipole moments are parallel and in opposite directions. If this positions the drug such that other intermolecular interactions can take place between it and the target, the alignment is beneficial to both binding and activity. If not, then binding and activity may be weakened. Dipole-dipole interactions fall away from quickly with distance than electrostatic interactions, but less quickly than van der Waals interactions.
What is an ion-dipole interaction? Stronger than a dipole-dipole interaction, this occurs between a charged or ionic group in one molecule that interacts with a dipole in a second molecule. It also falls off less rapidly with separation.
Describe an example of an induced dipole moment. There is evidence that an aromatic ring can interact with an ionic group such as a quaternary ammonium ion - such an interaction is feasible if the positive charge of the quaternary ammonium group distorts the π electron cloud of the aromatic ring to produce a dipole moment where the face of the aromatic ring is electron-rich and the edges are electron-deficient. This is a cation-pi interaction, the type that acetylcholine forms with its binding sites.
What are repulsive interactions? If molecules come too close, their molecular orbitals start to overlap and this results in repulsion - this is significant because otherwise molecules would have nothing to stop them merging with each other. One example is two groups of identical charge repelling each other.
What is the importance of water in drug-target interactions? Drug targets exist in water in the aqueous environment of the body, and drug molecules must travel through this environment - so both are solvated in water molecules before they meet. It is important for the energy required to remove these water molecules to be less than the stabilisation energy gained by the binding interactions or the drug may be ineffective.
What structural adjustments may need to be made to a drug molecule in order to reduce its energy of desolvation (removal of H2O)? Polar groups may need to be removed in order to reduce its energy of desolvation (removing water), but sometimes polar groups are added to a drug to increase its water solubility - in these cases it is important that such groups are positioned so that they protrude from the binding site when the drug binds and are solvent accessible.
Next to a non-polar surface, water molecules are more ordered as they form stronger reactions with each other in order to avoid the non-polar region. What does this mean for entropy? What might change when a drug binds with its target on a non-polar surface? This more ordered configuration results in negative entropy. When the hydrophobic region of a drug reacts with a hydrophobic region of a binding site, these water molecules are freed and become less ordered, leading to an increase in entropy which may be small individually but can be substantial overall.
Show full summary Hide full summary

Similar

Ionic Bondic Flashcards.
anjumn10
WJEC Level 2 Latin Language Vocabulary (A)
Gian Hernandez
WJEC Level 2 Latin Language Vocabulary (T)
Gian Hernandez
WJEC Level 2 Latin Language Vocabulary (E&F)
Gian Hernandez
Health & Safety Quiz
Peter Cunningham
WJEC Level 2 Latin Language Vocabulary (S)
Gian Hernandez
WJEC Level 2 Latin Language Vocabulary (N)
Gian Hernandez
WJEC Level 2 Latin Language Vocabulary (M)
Gian Hernandez
WJEC Level 2 Latin Language Vocabulary (I)
Gian Hernandez
6.4 Hydrogen Bonding
Bee Brittain
Chemistry Unit 1,2,3 Test
Bohdan Hrotovytskyy