Flashcards in Medicine: Medicinal Chemistry and the drug development process Deck (43):
What is medicinal chemistry?
Medicinal Chemistry is a multidisciplinary science aimed at the design and synthesis of new chemical entities in order to generate new medicines for the diagnosis, prevention and treatment of disease.
Name some drug targets
- Nucleic Acids
Name some ways leads are discovered or brought up as ideas
-Leads from nature or folk remedies
What is a Pharmacophore?
Identification of the structural elements within a compound that confers beneficial activity; called its Pharmacophore
edits to pharmacophore that drug companies do?
Changes to chemical structure that can change activity: Potency, ADME, toxicology
Changing the size and shape of the molecule
New substituents to alter receptor/enzyme binding or changing water solubility
Restriction of conformation
Replacement of functional groups with active mimics, known as bioisosteres.
4 types of ways drugs can bind to their target
Electrostatic or Ionic bonds
Van der Waals interactions
Dipole-dipole, ion-dipole and induced dipole interactions
How strong are ionic bonds? In what conditions are they stronger?
Strongest of the intermolecular bonds (20-40 kJ mol-1)
The strength of interaction drops off less rapidly with distance than with other forms of intermolecular interactions
Stronger interactions occur in hydrophobic environments
Do hydrogen bonds vary in strength?
Why is an amide N not likely to participate in an ionic or hydrogen bond?
lone pair is delocalized.
2 examples of strong hydrogen bond acceptors
carboxylate ion, phosphate ion
6 examples of moderate hydrogen bond acceptors
carboxylic acid, amide oxygen, ketone, ester, ether, alcohol
6 examples of poor hydrogen bond acceptors
sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic amine
One example of a good hydrogen bond donor
Quaternary ammonium ion
Describe the strength of hydrogen bonds in relation to other types of bonds
Weaker than electrostatic interactions but stronger than van der Waals interactions
How are hydrogen bonds formed?
A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (N or O)
The electron deficient hydrogen is usually attached to a heteroatom (O or N)
What is a hydrogen bond acceptor?
The electron rich heteroatom is called a hydrogen bond acceptor
what is a hydrogen bond donor?
The electron deficient hydrogen is called a hydrogen bond donor
Where do ionic bonds take place?
Takes place between groups of opposite charge
Strength of ionic bond in relation to the distance between the two charged groups?
The strength of the ionic interaction is inversely proportional to the distance between the two charged groups
Most important interactions as a drug enters the binding site?
How strong are van der Waals forces?
Very weak interactions (2-4 kJmol-1)
How do van der Waals forces occur?
Occur between hydrophobic regions of the drug and the target
Due to transient areas of high and low electron densities leading to temporary dipoles
How do van der Waals bond strength respond to distance?
Interactions drop off rapidly with distance
Drug must be close to the binding region for interactions to occur
Are van der Waals forces important in drug binding?
Although weak bonds separately, the overall contribution of van der Waals interactions can be crucial to binding
When can dipole-dipole reactions occur?
if the drug and the binding site have dipole moments
How do dipole-dipole forces occur?
Dipoles align with each other as the drug enters the binding site
Dipole alignment orientates the molecule in the binding site
Referring to dipole-dipole bonding, when is orientation beneficial?
if other binding groups are positioned correctly with respect to the corresponding binding regions
Referring to dipole-dipole bonding, when is orientation detrimental?
if the binding groups are not positioned correctly with respect to corresponding binding regions
How do dipole-dipole bonds change with distance in comparison to electrostatic and van der Waals interactions?
The strength of the interaction decreases with distance more quickly than with electrostatic interactions, but less quickly than with van der Waals interactions
When do ion-dipole interactions occur?
Occur where the charge on one molecule interacts with the dipole moment of another
Describe the strength of ion-dipole interactions compared to that of dipole-dipole interactions
Stronger than a dipole-dipole interaction
Strength of interaction falls off less rapidly with distance than for a dipole-dipole interaction
When do induced dipole reactions occur?
Occur where the charge on one molecule induces a dipole on another
Occurs between a quaternary ammonium ion and an aromatic ring
When and how do hydrophobic reaction occur?
Hydrophobic regions of a drug and its target are not solvated
Water molecules interact with each other and form an ordered layer next to hydrophobic regions - negative entropy
Interactions between the hydrophobic interactions of a drug and its target ‘free up’ the ordered water molecules
Results in an increase in entropy
Beneficial to binding energy
What is QSAR
Quantitative Structure/Activity Relationships
What is the most important physical property affecting potency, distribution and elimination
What does lipophilicity affect?
- receptor/enzyme binding
- plasma protein binding
Describe ethers, chloroform and halothane in relation to their potency
ether < chloroform < halothane
What are Hammett constants (σx) ?
These are measure of the electron donating or withdrawing power of a substituent; derived initially from substituted benzoic acids.
Give the equation relating to Hammett constants
σx = pKa (substituted acid) – pKa (unsubstituted acid)
Which of the following will partition into the phospholipid bilayer
An ionised compound or an unionised one?
Only the unionised one
According to this approximation, the drug needs to be in its uncharged (i.e. UNIONISED) form at the membrane surface to permeate the membrane by PASSIVE DIFFUSION
The concentration of the compound passing through the membrane barrier depends upon what?
The percentage of the compound which is unionised
The % of UNONISED compound is controlled by what?
its pKa and the pH of the solution