Medicinal chemistry and biophysics
Lecture 1: Introduction
In the years, more biologic agents are coming up as medicines. The FDA approval
numbers are low. That is because:
- Expensive to go from bench to bedside
- Unpredictable effects
- Handling molecular events in crowded systems
- Geopolitics (nothing is spent on antimalarial medicines because people with
Malaria cannot afford it)
- Choice of target areas
- Rare/orphan diseases (makes it more complex to design a drug)
Medicinal chemistry is highly interdisciplinary, should have knowledge about:
- Physical/chemical properties of drugs
- Stability of drugs
- Absorption and excretion
- Metabolism
- Formulation of drugs (administration)
- Quality control
- Analysis of drugs and their metabolites
- Biophysics = use of light, sound or particle emission to study a sample
Unstable (protein without ligand) at the top, stable (protein with ligand) at the bottom
,The 3D structure determines the biological activity of drugs:
- Membrane passage
o Mostly passive -> can be predicted by
log P value, pH of solute chosen to
generate neutral molecules
o Active -> relies on molecular recognition (shape) by transport proteins
- Binding to targets
- Metabolism
- Pharmacokinetics
Lipinski’s rule of five (good absorption requires good solubility in membranes and
water):
- Molecular mass less than 500 (learn molecular masses)
- Log P less than 5
- Less than ten hydrogen bond acceptors (-O-, -N-, etc)
- Less than five hydrogen bond donors (NH, OH, etc)
Example:
MW = 499 kDa
HBA = 7
HBD = 2
LogP = 4.49 -> how many more times soluble
is this in water than in membranes (30000x)
Reminder: lipids are polar and hydrophobic
Bodies do not act if they are not bound (the exception for this idea is alcohol)
Induced fit = enzyme changes shape slightly as substrate enters active site, making the
fit more precise
The more stable the products the more there is
present at equilibrium
Covalent -> permanently, no dissociation so no
equilibrium
,Example:
(G) = Gibbs Free energy = energy required to build the system from nothing/vacuum
1. a and b (reactions that will
end on a lower energy state)
2. a (smallest hill to get over
and will occur naturally)
3. b (largest drop)
The higher the hill (intermediate level), the less likely it is that the reaction will go like
that. So lower hill will go faster.
Drug design is about making ΔG as small as possible (you want it to be negative to occur
naturally)
Enthalpy = ΔH (reaction is endothermic when >0, reaction is exothermic when <0) =
hbonds
Entropy = ΔS = measure of ordering of the system =
hydrophobic interactions
, ion-ion interactions: geometry plays a role,
contributes to enthalpy
ion-ion dipole interactions: geometry plays a
role, contributes to enthalpy
hydrophobic interactions: entropy is driving
force, geometry less important
Reduced ligand flexibility -> lower entropy
Removal of solvation shell -> increases entropy
There is no strong correlation, but the trend seems to be that
more buried hydrophobic surface leads to stronger binding
Enthalpy-entropy compensation = weaker ionic interactions
(ΔH) can be compensated for by improved hydrophobics (ΔS) and vice versa
ΔG and ΔG are cumulative -> ΔΔG
Lecture 1: Introduction
In the years, more biologic agents are coming up as medicines. The FDA approval
numbers are low. That is because:
- Expensive to go from bench to bedside
- Unpredictable effects
- Handling molecular events in crowded systems
- Geopolitics (nothing is spent on antimalarial medicines because people with
Malaria cannot afford it)
- Choice of target areas
- Rare/orphan diseases (makes it more complex to design a drug)
Medicinal chemistry is highly interdisciplinary, should have knowledge about:
- Physical/chemical properties of drugs
- Stability of drugs
- Absorption and excretion
- Metabolism
- Formulation of drugs (administration)
- Quality control
- Analysis of drugs and their metabolites
- Biophysics = use of light, sound or particle emission to study a sample
Unstable (protein without ligand) at the top, stable (protein with ligand) at the bottom
,The 3D structure determines the biological activity of drugs:
- Membrane passage
o Mostly passive -> can be predicted by
log P value, pH of solute chosen to
generate neutral molecules
o Active -> relies on molecular recognition (shape) by transport proteins
- Binding to targets
- Metabolism
- Pharmacokinetics
Lipinski’s rule of five (good absorption requires good solubility in membranes and
water):
- Molecular mass less than 500 (learn molecular masses)
- Log P less than 5
- Less than ten hydrogen bond acceptors (-O-, -N-, etc)
- Less than five hydrogen bond donors (NH, OH, etc)
Example:
MW = 499 kDa
HBA = 7
HBD = 2
LogP = 4.49 -> how many more times soluble
is this in water than in membranes (30000x)
Reminder: lipids are polar and hydrophobic
Bodies do not act if they are not bound (the exception for this idea is alcohol)
Induced fit = enzyme changes shape slightly as substrate enters active site, making the
fit more precise
The more stable the products the more there is
present at equilibrium
Covalent -> permanently, no dissociation so no
equilibrium
,Example:
(G) = Gibbs Free energy = energy required to build the system from nothing/vacuum
1. a and b (reactions that will
end on a lower energy state)
2. a (smallest hill to get over
and will occur naturally)
3. b (largest drop)
The higher the hill (intermediate level), the less likely it is that the reaction will go like
that. So lower hill will go faster.
Drug design is about making ΔG as small as possible (you want it to be negative to occur
naturally)
Enthalpy = ΔH (reaction is endothermic when >0, reaction is exothermic when <0) =
hbonds
Entropy = ΔS = measure of ordering of the system =
hydrophobic interactions
, ion-ion interactions: geometry plays a role,
contributes to enthalpy
ion-ion dipole interactions: geometry plays a
role, contributes to enthalpy
hydrophobic interactions: entropy is driving
force, geometry less important
Reduced ligand flexibility -> lower entropy
Removal of solvation shell -> increases entropy
There is no strong correlation, but the trend seems to be that
more buried hydrophobic surface leads to stronger binding
Enthalpy-entropy compensation = weaker ionic interactions
(ΔH) can be compensated for by improved hydrophobics (ΔS) and vice versa
ΔG and ΔG are cumulative -> ΔΔG
