Medicine: Medicinal Chemistry and the drug development process Flashcards Preview

Pharmacy Year 2 Semester 1 > Medicine: Medicinal Chemistry and the drug development process > Flashcards

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

-- Enzymes
-- Receptors
-- Transporters
- Nucleic Acids
- Carbohydrates
- Lipids


Name some ways leads are discovered or brought up as ideas

-Copying others
-Leads from nature or folk remedies
-Educated guessing
-Combinatorial libraries


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

Hydrogen 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?

because the
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?

Ionic bonds


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?

aqueous solubility
- permeability
- receptor/enzyme binding
- metabolism
- 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


Henderson-Hasselbach equation for a weak base

pH = pKa + log10[B]