GMS6504 #2 Questions And Answers With Verified Solutions
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GMS6504
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GMS6504
GMS6504 #2 Questions And Answers With Verified Solutions
what are the four things that make a good drug versus a bad one?
1. Lipinski's Rule of 5
2. Chemical reactivity: good or bad?
3. Some chemically or biologically reactive functional groups to recognize
4. Choosing a target
explain the ol...
GMS6504 #2 Questions And Answers With Verified
Solutions
what are the four things that make a good drug versus a bad one?
1. Lipinski's Rule of 5
2. Chemical reactivity: good or bad?
3. Some chemically or biologically reactive functional groups to recognize
4. Choosing a target
explain the old lipinskis rule of 5 and the rules
Poor absorption or permeation are more likely when:
1. Molecular mass greater than 500 Da (want small and absorbable)
2. High lipophilicity (expressed as LogP greater than 5) (often contributes to high metabolic turnover,
low solubility, and poor oral absorption. In addition, highly lipophilic compounds tend to bind to
hydrophobic targets other than the desired target, and, therefore, there is an increased risk of
promiscuity and toxicity.)
3. More than 5 hydrogen bond donors (OH, FH, NH: no more than 5)
4. More than 10 hydrogen bond acceptors (want no more than 10)
define the partition coefficient
The ratio of the equilibrium concentrations of a dissolved substance in a two-phase system
containing two largely immiscible solvents (water and n-octanol)
(refers to if the molecule prefers to be in water or oil)
what is the partition coefficient equation?
P= (C oct / C water)
,For the partition coefficient equation; part of the equation must change in order to be used in real life
and why is this?
Log P = (C oct / C water)
Since the differences are usually on a very large scale, Log10(P) is used. (usually is between 0 and
10)
what are the improved lipinski parameters ? (aka what they actually use now in pharmacology)
1. Partition coefficient log P in -0.4 to +5.6 range ( means a very large amount in 1-octanol and not a
lot in water)
2. Molar refractivity from 40 to 130 (It represents size and polarizability of a fragment or molecule.)
3. Molecular weight from 160 to 500 Da (so not toooo small but def not too big)
4. Number of atoms from 20 to 70 (includes H-bond donors [e.g.;OHs and NHs] and H-bond
acceptors [e.g.; Ns and Os]) (refers to weight too)
5. Polar surface area no greater than 140 Å2 (once again not too big)
explain the difference between CNS and NonCNS drugs and what trend/ why there is a difference
CNS wants smaller drugs, smaller polar surface area, this is due to the fact that CNS drugs must pass
through the BBB
explain the good and bad sides of chemical reactivity when it comes to drug design
1.Modification of Proteins and/or Nucleic Acids (bad b/c if its over modified cant be fixed and have
to wait for body to make new protiens ect.) (Bad if unanticipated and non-selective, but can be good
if selective)
2. Labile in Biological Systems (how it breaks down in the body/ a compound that undergoes
reactions with a relatively high rate of. substitution.)
- can be substitutions of Esters Amide Bonds *Disulfide Bonds
,-Bad (since a Compound may be degraded in vivo); but Good (because it Can be incorporated into
the design of pro-drugs) (you wanna get in, get activated, get breakdown)
what are some of the most common reactive functional groups
-epoxides (very reactive)
- Michael acceptors and beta heterosubstituted carbonyl compounds
explain the concept of pro drugs and and why it is used?
• Sometimes drugs are designed to make use of metabolic processes in order to generate their active
form.
• This is done in order to improve some selected property of the molecule, such as water solubility or
ability to cross a membrane, temporarily.
how do we choose the form of pro drug and what are some of the common ones?
the functional group is chosen based on what your drug already has
- Most common (biologically labile) functional groups utilized in prodrug design.
what is THE most common employed prodrug and why are they the most common?
• Esters are the most commonly employed prodrugs.
• Numerous catalytic esterases are present in vivo to hydrolyze simple esters.
, what is the un-druggable target and why
Ras because of the lack of potential inhibitor-binding regions and its picomolar affinity for GTP/GDP
what are the two easily druggable targets?
enzymes and cell surface receptors
explain the types of enzymes that are easy to target and why
Kinases, Phosphatases, Histone Deacetylases, Misc. Metabolic Enzymes
(Generally Cell Permeable Small Molecule Drugs)
explain the types of cell surface receptors and why they are easy to target and 3 examples
G-Protein Coupled Receptors, Receptor Tyrosine Kinases, Cytokine Receptors.
most common and easy to target bc naturally designed to have a ligand attach
These can be:
Cell Permeable Small Molecule Drugs that inhibit cytoplasmic enzyme domain
Monoclonal Antibodies that target the extracellular domain
Ligand binding site antagonists/inverse agonists
what are the two known Challenges to Pharmacological Intervention
1. "Undruggable" targets (transcription factors, scaffolding proteins, protein-protein interactions
involving large, flat protein-protein interfaces)
2. Restoring the function of a gene lost by mutation/deletion
what are the 5 -Approaches for drugging "undruggable" targets
a. Higher order complex formation (Rapamycin, FK506, Cyclosporine), "Chemobodies"
b. Synthetic lethality
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