Summary pharmacochemistry
1
,Chapter 1 Drugs and drug
targets: an overview
introduction
Medicinal chemistry involves the design and synthesis of a pharmaceutical agent that has a desired
biological effect on the human body or some other living system.
Key points 1.1
Drugs are compounds that interact with a biological system to produce a biological response
No drug is totally safe. Drugs vary in the side effects they might have.
The dose level of a compound determines whether it will act as a medicine or as a poison
the therapeutic index is a measure of a drug’s beneficial effect at a low dose versus its
harmful effects at a higher dose. A high therapeutic index indicates a large safety margin
between beneficial and toxic doses.
The principle of selective toxicity means that useful drugs show toxicity against foreign or
abnormal cells, but not against normal host cells.
Drug targets
The specific effects that a drug has is more a result of where it acts in the body – the drug targets
affinity for certain target due to structure.
The main molecular targets for drugs are proteins and nucleic acids which are macromolecules
drug that is much smaller, usually interacts with these macromolecules at a specific area known as
the binding site
some drugs react with the binding site and become permanently attached via a covalent
bond
most drugs interact through weaker forms of interaction known as intermolecular bonds
electrostatic or ionic bonds
dipole-dipole interactions
hydrogen bonds
van der Waals interactions
hydrophobic interactions
The intermolecular bonds between a drug and the target is not as strong as a
covalent bond and is therefore reversible This means that an equilibrium takes
place between the drug being bound and unbound to its target
Strong enough to hold the drug for a certain time to have an effect on the target but
weak enough to allow it to depart once it has done its job
o The time that a drug remains at its target will depend on the number of
intermolecular bonds involved in holding it there
o The relative strength of the different intermolecular binding forces is also an
important factor
Functional groups present in the drug may be important for intermolecular
bond formation if they do these are called binding groups
as well as the carbon skeleton of the drug forms van der Waals
interactions
Also the target binding site contains functional groups and carbon skeletons to form
intermolecular bonds with ‘visiting’ drugs specific regions where this takes place
are known as binding regions: important for pharmacodynamics
2
,Intermolecular bonding forces
The number and the types of bonds that a drug forms depends on the groups present in it, and thus
on its’ structure determines its affinity for macromolecules; and what it is most likely to target
Electrostatic interactions
electrostatic interactions: strongest intermolecular bond that takes place between groups
having opposite charges
stronger in hydrophobic environments than in polar ones
Binding sites of macromolecules usually more hydrophobic than the surface
enhances the effect of an ionic interaction (stronger)
Drop-off in ionic strength with separation less than in other intermolecular
interactions, so if an ionic interaction is possible, it is likely to be the most important
initial interaction as the drug enters the binding site strongest long-range
(=passing by) interaction strength to “halt” the molecule at the target
hydrogen bonds
Hydrogen bonds: take place between a hydrogen bond donor (HBD) and a hydrogen bond
acceptor (HBA), the more electropositive and the more electronegative atom (that has a lone
pair) respectively
Electrostatic attraction
weak σ bond formation because of orbital overlap directional consequence:
optimal orientation when angle between X,H and Y is 180 ◦, but can vary from 130 to
180 and 90 for weak H-bonds
directionality also a result from bond acceptor hybridisation
Both the strength of the HBA and the HBD influence interaction strength, as these determine the
interaction efficiency:
HBA:
sulphur atoms are less EN than O and N atoms because 3S orbital larger thus
more diffuse charge, lower charge density in the overlap: less efficient interaction
if lone pairs on HBA are delocalised less efficient interaction
HBD:
the HBD becomes stronger the more electronegative the hydrogen-neighbouring
atom becomes:
example: an H bound to >N+< is a stronger donor than one to -N< because the
former is more EN
Van der Waals interactions
Van der Waals interactions are very weak interactions involve interactions between hydrophobic
regions of different molecules
Neutral electron distribution, non-polar regions never totally even or symmetrical, always
transient areas of high and low electron densities leading to temporary dipoles dipole in
one molecule can induce dipole on another molecule
Area of high electron density can have an attraction for an area of low electron density
3
, Fast drop-off of strength of this type of interaction drug must be close to the binding site
before these interactions become important
Dipole-dipole and dipole-ion interactions
Different ENs of atoms and functional groups present lead to permanent dipole moments target
has functional groups as well so it is inevitable that it has various local dipole moments
dipole moments on drug and target possibly interact as drug approaches alignment of
dipole moments in parallel and opposite fashion: influences binding orientation may be
beneficial to binding and activity of the drug if this allows for more interactions
interaction strength drop off: electrostatic < dipole < van der Waals
ion-dipole interaction is stronger than a dipole-dipole interaction
cation-pi interaction if the cation induces a distortion in the pi cloud that produces a dipole
ACh forms this interaction with its target
The effect of water and hydrophobic interactions
The body is an aqueous environment in which drugs, as well as the target are dissolved. In order for
these two to interact with each other, these water molecules must be stripped off costs energy
if Edesolvation > Estabilisation , the drug may be ineffective polar groups make interaction with
water stronger, and thus have higher desolvation energy, but these increase solubility
As polar groups tho increase solubility, it is thus most beneficial to position these
protruding from the binding site when the drug binds water does not have to be
stripped away
hydrophobic regions cause formation of a hydration shell decrease of ΔH but large
decrease in ΔS as well interaction with target favourable if ΔG is lower compared to non-
interaction: this is the case when the hydration shell is broken (large increase in ΔS) and if
the decrease in ΔH is being compensated by the formation of hydrophobic interactions (still
lowering ΔH)
4
1
,Chapter 1 Drugs and drug
targets: an overview
introduction
Medicinal chemistry involves the design and synthesis of a pharmaceutical agent that has a desired
biological effect on the human body or some other living system.
Key points 1.1
Drugs are compounds that interact with a biological system to produce a biological response
No drug is totally safe. Drugs vary in the side effects they might have.
The dose level of a compound determines whether it will act as a medicine or as a poison
the therapeutic index is a measure of a drug’s beneficial effect at a low dose versus its
harmful effects at a higher dose. A high therapeutic index indicates a large safety margin
between beneficial and toxic doses.
The principle of selective toxicity means that useful drugs show toxicity against foreign or
abnormal cells, but not against normal host cells.
Drug targets
The specific effects that a drug has is more a result of where it acts in the body – the drug targets
affinity for certain target due to structure.
The main molecular targets for drugs are proteins and nucleic acids which are macromolecules
drug that is much smaller, usually interacts with these macromolecules at a specific area known as
the binding site
some drugs react with the binding site and become permanently attached via a covalent
bond
most drugs interact through weaker forms of interaction known as intermolecular bonds
electrostatic or ionic bonds
dipole-dipole interactions
hydrogen bonds
van der Waals interactions
hydrophobic interactions
The intermolecular bonds between a drug and the target is not as strong as a
covalent bond and is therefore reversible This means that an equilibrium takes
place between the drug being bound and unbound to its target
Strong enough to hold the drug for a certain time to have an effect on the target but
weak enough to allow it to depart once it has done its job
o The time that a drug remains at its target will depend on the number of
intermolecular bonds involved in holding it there
o The relative strength of the different intermolecular binding forces is also an
important factor
Functional groups present in the drug may be important for intermolecular
bond formation if they do these are called binding groups
as well as the carbon skeleton of the drug forms van der Waals
interactions
Also the target binding site contains functional groups and carbon skeletons to form
intermolecular bonds with ‘visiting’ drugs specific regions where this takes place
are known as binding regions: important for pharmacodynamics
2
,Intermolecular bonding forces
The number and the types of bonds that a drug forms depends on the groups present in it, and thus
on its’ structure determines its affinity for macromolecules; and what it is most likely to target
Electrostatic interactions
electrostatic interactions: strongest intermolecular bond that takes place between groups
having opposite charges
stronger in hydrophobic environments than in polar ones
Binding sites of macromolecules usually more hydrophobic than the surface
enhances the effect of an ionic interaction (stronger)
Drop-off in ionic strength with separation less than in other intermolecular
interactions, so if an ionic interaction is possible, it is likely to be the most important
initial interaction as the drug enters the binding site strongest long-range
(=passing by) interaction strength to “halt” the molecule at the target
hydrogen bonds
Hydrogen bonds: take place between a hydrogen bond donor (HBD) and a hydrogen bond
acceptor (HBA), the more electropositive and the more electronegative atom (that has a lone
pair) respectively
Electrostatic attraction
weak σ bond formation because of orbital overlap directional consequence:
optimal orientation when angle between X,H and Y is 180 ◦, but can vary from 130 to
180 and 90 for weak H-bonds
directionality also a result from bond acceptor hybridisation
Both the strength of the HBA and the HBD influence interaction strength, as these determine the
interaction efficiency:
HBA:
sulphur atoms are less EN than O and N atoms because 3S orbital larger thus
more diffuse charge, lower charge density in the overlap: less efficient interaction
if lone pairs on HBA are delocalised less efficient interaction
HBD:
the HBD becomes stronger the more electronegative the hydrogen-neighbouring
atom becomes:
example: an H bound to >N+< is a stronger donor than one to -N< because the
former is more EN
Van der Waals interactions
Van der Waals interactions are very weak interactions involve interactions between hydrophobic
regions of different molecules
Neutral electron distribution, non-polar regions never totally even or symmetrical, always
transient areas of high and low electron densities leading to temporary dipoles dipole in
one molecule can induce dipole on another molecule
Area of high electron density can have an attraction for an area of low electron density
3
, Fast drop-off of strength of this type of interaction drug must be close to the binding site
before these interactions become important
Dipole-dipole and dipole-ion interactions
Different ENs of atoms and functional groups present lead to permanent dipole moments target
has functional groups as well so it is inevitable that it has various local dipole moments
dipole moments on drug and target possibly interact as drug approaches alignment of
dipole moments in parallel and opposite fashion: influences binding orientation may be
beneficial to binding and activity of the drug if this allows for more interactions
interaction strength drop off: electrostatic < dipole < van der Waals
ion-dipole interaction is stronger than a dipole-dipole interaction
cation-pi interaction if the cation induces a distortion in the pi cloud that produces a dipole
ACh forms this interaction with its target
The effect of water and hydrophobic interactions
The body is an aqueous environment in which drugs, as well as the target are dissolved. In order for
these two to interact with each other, these water molecules must be stripped off costs energy
if Edesolvation > Estabilisation , the drug may be ineffective polar groups make interaction with
water stronger, and thus have higher desolvation energy, but these increase solubility
As polar groups tho increase solubility, it is thus most beneficial to position these
protruding from the binding site when the drug binds water does not have to be
stripped away
hydrophobic regions cause formation of a hydration shell decrease of ΔH but large
decrease in ΔS as well interaction with target favourable if ΔG is lower compared to non-
interaction: this is the case when the hydration shell is broken (large increase in ΔS) and if
the decrease in ΔH is being compensated by the formation of hydrophobic interactions (still
lowering ΔH)
4
