MEDICINAL CHEMISTRY AND BIOPHYSICS
The system moves from a higher energy level at 32.000 to a lower energy
level at 24.000, with an energy difference of -8000. This corresponds to an
energy release.
Lower energy levels represent more stable states, while higher energy
levels are typically less stable and temporary. Systems in higher energy
states tend to return to lower, more stable states by releasing energy.
The 3D structure determines the biological activity of drugs:
• Membrane passage
• Binding to targets
• Metabolism
• Pharmacokinetics
After administration, most drugs have to travel through various tissues and cell
membranes to reach their target site. Cell membranes are primarily made of lipid
bilayers, which act as barriers to many substances. For a drug to work effectively, it
needs to cross these membranes, either by passive diffusion or through active
transport mechanisms.
Passive diffusion is the process by which drugs move across the membrane from an
area of higher concentration to an area of lower concentration, without requiring
energy. Whether a drug can pass through the membrane by passive diffusion
depends on its lipophilicity (fat solubility). The log P value is used to estimate this.
Log P is the partition coefficient, which compares how a drug distributes between a
lipid (fat) phase and a water phase. It reflects the balance between the drug's
hydrophilic and hydrophobic properties. A drug with a high log P is more
lipophilic, meaning it can easily dissolve in and pass through the lipid bilayer of cell
membranes. In contrast, a low log P value indicates that the drug is more hydrophilic,
making it less likely to pass through the lipid membrane by passive diffusion.
Drugs with moderate log P values are usually best suited for passive diffusion. If a
drug is too hydrophilic, it won't easily cross the lipid membrane. On the other hand, if
it's too lipophilic, it may get stuck in the membrane and not reach the inside of the cell
effectively.
Some drugs cannot rely on passive diffusion due to their size, polarity, or chemical
properties. In such cases, active transport comes into play. Active transport involves
transport proteins that recognize and bind specific molecules and actively transport
them across the membrane, often against their concentration gradient. This process
requires energy (ATP).
For active transport, the drug must have the correct shape and structure to fit into
the transport protein. Many polar or charged drugs use active transport to cross
membranes because they can't pass through the lipid bilayer on their own.
Most drugs rely on passive diffusion to cross cell membrane.
1
,Amphiphilic drugs, with both hydrophilic and lipophilic properties, have a versatile
drug delivery.
[𝐝𝐫𝐮𝐠]𝐨𝐜𝐭𝐚𝐧𝐨𝐥
Log P = Log10 ( [𝐝𝐫𝐮𝐠]𝐰𝐚𝐭𝐞𝐫 )
• High log P (>1): The drug is more lipophilic, meaning it prefers to dissolve in
lipid environments like cell membranes.
• Low log P (<1): The drug is more hydrophilic, meaning it prefers aqueous
environments like blood or extracellular fluid.
• log P ≈ 1: The drug has a balanced affinity for both water and lipids.
Thus the Log P is used as a measure of lipophilicity.
The pH of the solute is chosen to generate neutral molecules.
Lipinski's Rule of Five is a set of guidelines used in medicinal chemistry to predict the
oral bioavailability of a drug, meaning how well a drug can be absorbed in the
human body when taken orally.
Lipinski’s Rule of Five:
• Molecular mass less than 500
• Log P less than 5
• Less than 10 hydrogen bond acceptors (-O-, -N-, etc)
• Less than 5 hydrogen bond donors (OH, NH, etc)
A good absorption requires good solubility in both water and in membranes.
Example: Does this drug obey Lipinski?
Molecular weights:
• C = 12 → 24 x 12 = 288
• N = 14 → 7 x 14 = 98
• H = 1 → 29 x 1 = 29
• O = 16 → 2 x 16 = 32
Total MW: 288 + 98 + 29 + 32 = 447
An H-bond donor is typically a hydrogen atom that is covalently bonded to a highly
electronegative atom, usually N or O. These atoms can donate hydrogen atoms to
form hydrogen bonds with acceptor atoms in other molecules. Look for –OH, –NH
and -NH2.
• Red arrows = 2
An H-bond acceptor is an electronegative atom with lone pairs of electrons (double
bond) that can form hydrogen bonds with hydrogen atoms from H-bond donors. Look
for =O and =N.
• Blue arrows = 7
2
,Log P = 4.49
How many times more soluble is this in membranes than in water?
10LogP = 104.49 = ~30000x
Yes, this drug obeys Lipinski!
The phospholipid bilayer is the fundamental structure of cell
membranes. The phospholipid bilayer has two layers of
phospholipids with the hydrophilic heads facing outward
toward water, and the hydrophobic tails facing inward, forming
a non-polar core.
Paul Ehrlich introduced the idea that the biological effect of
almost all compounds was due to its binding to a target. However, there is no
receptor for alcohol.
Drugs bind to their target molecules (such as receptors or enzymes) following the
Lock and Key principle. In this model, the drug (key) fits precisely into the specific
site on the target molecule (lock), ensuring selective binding and interaction. This
explains the specificity of drug action, where only certain drugs can bind to certain
targets based on their shapes and chemical compatibility.
The Induced Fit model expands on the Lock and Key principle, explaining that drug
binding is a dynamic process. When a drug approaches its target, the target
molecule undergoes a slight conformational change to accommodate the drug
more effectively. This dynamic adaptation makes the fit more precise.
Thermodynamics:
• Equilibrium state
• K
K is the equilibrium constant, which indicates the ratio of products to reactants at
equilibrium.
The more stable the products are, the more there is present at equilibrium.
3
, Kinetics:
• Rate of the process
• k (rate constant)
k is the rate constant, which defines how fast the reaction progresses toward
equilibrium.
Thermodynamics tells us where a reaction will end up (equilibrium), while kinetics
tells us how fast it will get there.
Types of interaction:
• Covalent
• Non-covalent
For a covalent interaction, there is only association
(kass). Dissociation doesn’t occur! There is thus no
equilibrium, only a (kinetic) rate.
For a non-covalent interaction, there is both association
and dissociation (kass and kdiss). An equilibrium can be
established.
Based on these values, the Ka and Kd can be calculated. Ka stands for the acid
dissociation constant. A larger Ka value indicates a stronger acid, meaning it
dissociates more completely. A smaller Ka value corresponds to a weaker acid,
meaning it dissociates less in solution. Kd refers to the dissociation constant in the
context of binding reactions. A lower Kd means stronger binding affinity, while higher
Kd means weaker binding affinity.
1 1
Ka = Kd → Kd = Ka
4
The system moves from a higher energy level at 32.000 to a lower energy
level at 24.000, with an energy difference of -8000. This corresponds to an
energy release.
Lower energy levels represent more stable states, while higher energy
levels are typically less stable and temporary. Systems in higher energy
states tend to return to lower, more stable states by releasing energy.
The 3D structure determines the biological activity of drugs:
• Membrane passage
• Binding to targets
• Metabolism
• Pharmacokinetics
After administration, most drugs have to travel through various tissues and cell
membranes to reach their target site. Cell membranes are primarily made of lipid
bilayers, which act as barriers to many substances. For a drug to work effectively, it
needs to cross these membranes, either by passive diffusion or through active
transport mechanisms.
Passive diffusion is the process by which drugs move across the membrane from an
area of higher concentration to an area of lower concentration, without requiring
energy. Whether a drug can pass through the membrane by passive diffusion
depends on its lipophilicity (fat solubility). The log P value is used to estimate this.
Log P is the partition coefficient, which compares how a drug distributes between a
lipid (fat) phase and a water phase. It reflects the balance between the drug's
hydrophilic and hydrophobic properties. A drug with a high log P is more
lipophilic, meaning it can easily dissolve in and pass through the lipid bilayer of cell
membranes. In contrast, a low log P value indicates that the drug is more hydrophilic,
making it less likely to pass through the lipid membrane by passive diffusion.
Drugs with moderate log P values are usually best suited for passive diffusion. If a
drug is too hydrophilic, it won't easily cross the lipid membrane. On the other hand, if
it's too lipophilic, it may get stuck in the membrane and not reach the inside of the cell
effectively.
Some drugs cannot rely on passive diffusion due to their size, polarity, or chemical
properties. In such cases, active transport comes into play. Active transport involves
transport proteins that recognize and bind specific molecules and actively transport
them across the membrane, often against their concentration gradient. This process
requires energy (ATP).
For active transport, the drug must have the correct shape and structure to fit into
the transport protein. Many polar or charged drugs use active transport to cross
membranes because they can't pass through the lipid bilayer on their own.
Most drugs rely on passive diffusion to cross cell membrane.
1
,Amphiphilic drugs, with both hydrophilic and lipophilic properties, have a versatile
drug delivery.
[𝐝𝐫𝐮𝐠]𝐨𝐜𝐭𝐚𝐧𝐨𝐥
Log P = Log10 ( [𝐝𝐫𝐮𝐠]𝐰𝐚𝐭𝐞𝐫 )
• High log P (>1): The drug is more lipophilic, meaning it prefers to dissolve in
lipid environments like cell membranes.
• Low log P (<1): The drug is more hydrophilic, meaning it prefers aqueous
environments like blood or extracellular fluid.
• log P ≈ 1: The drug has a balanced affinity for both water and lipids.
Thus the Log P is used as a measure of lipophilicity.
The pH of the solute is chosen to generate neutral molecules.
Lipinski's Rule of Five is a set of guidelines used in medicinal chemistry to predict the
oral bioavailability of a drug, meaning how well a drug can be absorbed in the
human body when taken orally.
Lipinski’s Rule of Five:
• Molecular mass less than 500
• Log P less than 5
• Less than 10 hydrogen bond acceptors (-O-, -N-, etc)
• Less than 5 hydrogen bond donors (OH, NH, etc)
A good absorption requires good solubility in both water and in membranes.
Example: Does this drug obey Lipinski?
Molecular weights:
• C = 12 → 24 x 12 = 288
• N = 14 → 7 x 14 = 98
• H = 1 → 29 x 1 = 29
• O = 16 → 2 x 16 = 32
Total MW: 288 + 98 + 29 + 32 = 447
An H-bond donor is typically a hydrogen atom that is covalently bonded to a highly
electronegative atom, usually N or O. These atoms can donate hydrogen atoms to
form hydrogen bonds with acceptor atoms in other molecules. Look for –OH, –NH
and -NH2.
• Red arrows = 2
An H-bond acceptor is an electronegative atom with lone pairs of electrons (double
bond) that can form hydrogen bonds with hydrogen atoms from H-bond donors. Look
for =O and =N.
• Blue arrows = 7
2
,Log P = 4.49
How many times more soluble is this in membranes than in water?
10LogP = 104.49 = ~30000x
Yes, this drug obeys Lipinski!
The phospholipid bilayer is the fundamental structure of cell
membranes. The phospholipid bilayer has two layers of
phospholipids with the hydrophilic heads facing outward
toward water, and the hydrophobic tails facing inward, forming
a non-polar core.
Paul Ehrlich introduced the idea that the biological effect of
almost all compounds was due to its binding to a target. However, there is no
receptor for alcohol.
Drugs bind to their target molecules (such as receptors or enzymes) following the
Lock and Key principle. In this model, the drug (key) fits precisely into the specific
site on the target molecule (lock), ensuring selective binding and interaction. This
explains the specificity of drug action, where only certain drugs can bind to certain
targets based on their shapes and chemical compatibility.
The Induced Fit model expands on the Lock and Key principle, explaining that drug
binding is a dynamic process. When a drug approaches its target, the target
molecule undergoes a slight conformational change to accommodate the drug
more effectively. This dynamic adaptation makes the fit more precise.
Thermodynamics:
• Equilibrium state
• K
K is the equilibrium constant, which indicates the ratio of products to reactants at
equilibrium.
The more stable the products are, the more there is present at equilibrium.
3
, Kinetics:
• Rate of the process
• k (rate constant)
k is the rate constant, which defines how fast the reaction progresses toward
equilibrium.
Thermodynamics tells us where a reaction will end up (equilibrium), while kinetics
tells us how fast it will get there.
Types of interaction:
• Covalent
• Non-covalent
For a covalent interaction, there is only association
(kass). Dissociation doesn’t occur! There is thus no
equilibrium, only a (kinetic) rate.
For a non-covalent interaction, there is both association
and dissociation (kass and kdiss). An equilibrium can be
established.
Based on these values, the Ka and Kd can be calculated. Ka stands for the acid
dissociation constant. A larger Ka value indicates a stronger acid, meaning it
dissociates more completely. A smaller Ka value corresponds to a weaker acid,
meaning it dissociates less in solution. Kd refers to the dissociation constant in the
context of binding reactions. A lower Kd means stronger binding affinity, while higher
Kd means weaker binding affinity.
1 1
Ka = Kd → Kd = Ka
4
