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Summary of all lectures Medicinal Chemistry and Biophysics
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Medicinal Chemistry and BiophysicsLecture 1: Introduction and Thermodynamics
Medicijnen oefenen biologische effecten uit, voor specifieke ziektebeelden is er behoefte aan
specifieke medicijnen.
Medicines are chemicals, interacting with proteins.
Medicines are small molecules:
- NCE: new chemical entities.
- BLA: biologics applications.
Medicinal Chemistry is highly interdisciplinary: Chemistry, Biochemistry, Physics, Biophysics, Biology.
Drug companies want to make money.
Medicinal Chemistry: chemistry plays a key role within the pharmacy. Chemical knowledge is
required to:
- To design and determine the physical/chemical properties of drugs.
- To gain insight into the stability of drugs.
- Absorption and excretion of drugs is partly determined by their chemical properties.
- Metabolism of drugs based is on (bio)chemical transformations.
- The formulation of drugs (administration).
- Quality control of medicines.
- The analysis of drugs and their metabolites.
Biophysics: is the use of light, sound or particle emission (waves) to study a (bio) sample.
Proteins are made of amino acids.
The 3D structure determines the biological activity of drugs:
- Membrane passage.
- Binding to targets.
- Metabolism.
- Pharmacokinetics.
Membranes are made of lipids; water cannot get through. The exterior side is polar, the interior side
is non-polar. Passive membrane passage can be estimated/predicted by the log P value, which is
defined by the physical/chemical properties of the drug. Active transport relies on molecular
recognition (shape) by transport proteins.
PH of solute chosen to generate neutral molecules.
Measure of lipophilicity.
,Lipinski’s rule of five:
- Molecular mass less than 500.
- Log(P) less than 5.
- Less than ten hydrogen bond acceptors (-O-, -N- etc).
- Less than five hydrogen bond donors (NH, OH etc).
The more charged a system → the worse the log(p) → the less effective the drug
→ drug design relays much more on H bonds than on charges
Good absorption requires good solubility in both water and in membranes.
Lipids contain a polar head group and a hydrophobic (non-polar) tail.
Drugs bind to targets:
Paul Ehrlich (1854 – 1915) introduced the idea that the biological effect of almost all compounds was
due to it binding to a target (no alcohol receptor). ‘’Bodies do not act if they are not bound.’’
Lock and key:
- Drugs bind to their target molecules (receptors, enzymes etc.) by the Lock and Key principle
– but the process of binding is dynamic
- First formulated in 1894 by Emil Fisher.
- Example of retinol bound to a transport protein.
Thermodynamics and kinetics: binding is described by the same laws as chemical reactions.
Thermodynamics:
- Describes the equilibrium state.
- Parameter → K.
Kinetics:
- Describes the rate (speed) of the process.
- Parameter → k.
The more stable the products, the more there is present at equilibrium.
Types of interaction:
Covalent:
- Association. →
- Dissociation does not occur.
- No equilibrium, only a (kinetic) rate.
,Non-covalent:
Energetic of drug: target interactions:
- Each new interaction provides a change in (delta G) the Gibbs free energy.
- Gibbs free energy (delta G) is the energy required to build the system from nothing.
For a system to happen: reaction has to move from a high affinity state to a low affinity state.
• Gibbs free energy must drop → larger drop = more successful reaction
Energetics of drug-receptor interactions:
Enthalpy (delta H) and entropy (delta S) are driving forces of a reaction.
Drug design is about making delta G as small as possible (-500).
a.As large as possible (+500) b.As small as possible (-500)
dH = H-bonds
-T x dS = hydrophobics (high in exothermic reaction)
Delta H > 0 (heat) energy is absorbed → reaction is endothermic.
Delta H < 0 (heat) is energy is released → reaction is exothermic.
Delta S (entropy) is a measure of the ordering of the system.
• Entropy up, in exothermic reaction
The speed of the reaction depends on the activation energy.
Negative Gibbs free energy → drugs will bind (heat negative, exothermic, energy release)
, 𝑫𝒆𝒍𝒕𝒂𝑮 = 𝑹 𝒙 𝑻 𝒙 𝒍𝒏(𝑲𝒅)
R = gas constant
T = absolute temperature
Non-covalent binding is achieved by many simultaneous interactions between the ligand and the
macromolecule.
Electrostatic interactions (ion-ion):
- Opposite charges attract. → dependent on distance
- Equal charges repel.
- Typical interaction energy 4-8 kcal/mol.
- Geometry plays an important role.
- Contributes to enthalpy.
Ion-ion dipole:
- Hydrogen bonds; specific orientations that can make H bonds (not distance dependent)
- 1-7 kcal/mol.
- Acceptor: O, N, F.
- Donors: OH and NH.
- Contributes to enthalpy.
- Geometry plays an important role.
Hydrophobic interactions (important for the folding of proteins):
- Entropy (solvation) is the driving force. 1 kcal/mol. Specific fit.
- Assembly with minimal disruption of the solvent.
- Hydrogen bonding networks.
- Contributes to the entropy.
- Geometry is less important.
Role of entropy in Binding:
- Through reduced ligand flexibility → lower entropy.
- Removal of solvation shell around both bindings’ partners → increases entropy.
Single bond in a molecule → free rotation possible: higher level of entropy and higher level of
disorder in solution, can occupy many states
• When its bound, cannot longer move → lost entropy
Contribution of hydrophobic interactions to binding: 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.
• Smaller dG → molecule binds more tightly
• Smaller -T x dS → adding of hydrophobic constituent
Modifications are cumulative:
- Different optimization routes may lead to the same molecule.
- The effect of two independent substituents is cumulative.
- We refer to a ΔΔG (a change in the ΔG).
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