Theme 6 Lecture 22 Flashcards
crys
What are the two key factors affecting aqueous solubility?
The polarity and the crystal lattice energy of the solid crystal form
groups
How can poor solubility in compounds be addressed?
Introducing new polar functional groups or disrupting crystal packing can improve solubility.
groups and mpt
What indicates high crystal lattice energy and how can it be disrupted?
High melting points often indicate high crystal lattice energy, which can be disrupted by incorporating functional groups to lower melting points and increase water solubility.
esters,phenyl ring,
What standard practices are used to reduce drug metabolism?
Practices include reducing lipophilicity, inverting stereochemistry, modifying the steric environment around labile regions, altering electronic characteristics, and introducing conformational constraints.
E.g. esters are prone to hydrolysis so can break it.
Phenyl ring can undergo oxidation to phenol and then conjugation phase 2
How does steric shielding affect metabolic stability?
Prevents access in the metabolic site therefore reducing metabolic stability
metabolic
What is the deuterium isotope effect in drug development?
The deuterium isotope effect involves substituting hydrogen with deuterium to enhance metabolic stability, leading to slower metabolism and improved drug performance.
hb,dd,pi-c,elec,hp,pol
What strategies are applied during lead optimization to optimize drug-target affinity?
Optimizing H-bonding, dipole-dipole, π-cation, electrostatic, and hydrophobic interactions by adjusting the size, orientation, and polarity of functional groups.
shapes,ed,pp
What are bioisosteres and how are they used in drug design?
Bioisosteres are compounds or groups with similar molecular shapes, electron distribution, and physical properties.
They are used to maintain pharmacological activitywhile altering physical or pharmaceutical properties.
Grimms, similar
What is the difference between classical and nonclassical bioisosteres?
Classical bioisosteres are based on Grimms hydride displacement law and include atoms, ions, or molecules with identical peripheral electron layers.
Nonclassical bioisosteres may not possess the same number of atoms or valence electrons but still result in similar pharmacological activity
original
What is scaffold hopping and when is it used?
Scaffold hopping aims to replace the non-pharmacophoric scaffold of a molecule to improve properties intellectual
Maintainins the original pharmacophoric elements’ orientation.
Exercise 2, F,Ring,N
What are three strategies used in the lead optimization of Maraviroc from the initial HTS hit?
Fluorine Introduction:A fluorine atom was introduced to improve metabolic stability due to its strong C-F bond and high electronegativity.
Ring System Modification: The original benzene ring was replaced with a tetrahydropyran ring to modify the molecule’s shape and electron distribution, potentially enhancing binding affinity and selectivity.
Addition of a Basic Nitrogen: A tertiary amine was added, likely to form ionic or hydrogen bonds with the target protein, increasing the compound’s potency and specificity.
motifs
What are privileged structures in medicinal chemistry?
Structural motifs that are able to bind to various pharmacological targets.
These are useful in finding sacffholds and for identifying new hits in drug discovery.
E,HBA,lip,meta
How does fluorine incorporation affect a lead molecule?
Highly electronegative (dipole-dipole)
Acts as a HBA
Lipophiciity increases
Metabolic stability
What does fluorine do to the aromatic ring?
Fluorine deactivates the ring towards oxidative metabolism due to electron withdrawing
What is the major difference between Log P and Log D in pharmacokinetics?
For LogP drug molecules are neutral in solution
For LogD it is ionised and unionised in sol (depends on the compounds pka and pH)
