GMS 6504 questions with 100% correct
answers!
Lipinski's rule of 5 - correct answer ✔✔- Poor absorption or permeation are more likely when:
1. mass greater than 500 Da
2. highly lipophilic - logP > 5
3. more than 5 hydrogen bond donors
4. more than 10 hydrogen bond acceptors
Partition coefficient - correct answer ✔✔p = C(octanol)/C(water)
- ratio of the equilibrium concentrations of dissolved substance in a two-phase system containing two
largely immiscible solvents (water & octanol)
- Log10(P)
Improved Lipinski Parameters - correct answer ✔✔1. Partition coefficient Log(P) -0.4-5.6 range
2. Molar refractivity from 40-130
3. Molecular weight from 160-500
4. Number of atoms from 20-70
5. Polar surface area no greater than 140 A^2
CNS Drugs - correct answer ✔✔- need lower Polar Surface Area (A^2) to cross BBB
Modification of Proteins and/or nucleic acids - correct answer ✔✔- bad if unanticipated & non-selective
- good if selective
Esters, amide bonds, & disulfide bonds - correct answer ✔✔- labile in biological systems
- esters most labile
- useful for creating pro-drugs but can be broken down in-vivo
,Esters - correct answer ✔✔- most commonly bound pro-drug incorporate
- body is full of esterases capable of breaking down into active form
Easily druggable targets - correct answer ✔✔- enzymes - kinases, phosphatases, histone deacetylases
- cell surface receptors - GPCRs, RTKs, cytokine receptors
Undruggable targets - correct answer ✔✔- transcription factors
- scaffolding proteins
- protein-protein interactions involving large, flat protein-protein interfaces
Undruggable approaches - correct answer ✔✔- higher order complex formation (rapamycin, FK506,
cyclosporine) - chemobodies
- Synthetic lethality
- RNAi/Antisense RNA
- genome editing (CRISPR)
- SAR by NMR
ATP inhibitors - correct answer ✔✔- ATP-competitive inhibitors are easy to design
- kinases are present in nearly all signalling pathways
- ATP kinase binding sites are evolutionarily conserved
- high functional redundancy among kinases
Gatekeeper - correct answer ✔✔- defines size of specificity pocket
- bigger the keeper smaller the size of the specificity pocket
Specificity pocket - correct answer ✔✔- varies in size amonnst different ATP sites
, Gatekeeper makeup - correct answer ✔✔- predomenently methionine, threonine, luecine, or
phenylanalnine
ATP-competitive kinse inhibitors - correct answer ✔✔- recognize the active conformation of kinase (type
1)
Irreversible kinase inhibitors - correct answer ✔✔- covalently react with cysteine residues within the
kinase near the atp binding site
Kd - correct answer ✔✔- dissociation constant
- concentration of a ligand where half of the binding sites on a protein are bound
- circle size is proportional to binding affinity
Difficult to develop specific active site kinase inhibitors - correct answer ✔✔- due to gatekeeper
mutations
- active site mutations
- resistance over time
- overexpression of kinase
- functional redundancy
William Coley - correct answer ✔✔- father of cancer immunotherapy
- developed concoction mixture of killed bacteria that was injected intratumorally, causing cancer
regression
- results were hard to duplicate due to Coley's poor record taking skills
Cross-presentation of tumor antigens - correct answer ✔✔- APCs pick up tumor antigens and present to
dendritic cells
- dendritic cells present tumor antigens and co-stimulators to CD8+ cells and induce tumor-targeted
execution
Bone marrow transplant - correct answer ✔✔- form of cancer immunotherapy
answers!
Lipinski's rule of 5 - correct answer ✔✔- Poor absorption or permeation are more likely when:
1. mass greater than 500 Da
2. highly lipophilic - logP > 5
3. more than 5 hydrogen bond donors
4. more than 10 hydrogen bond acceptors
Partition coefficient - correct answer ✔✔p = C(octanol)/C(water)
- ratio of the equilibrium concentrations of dissolved substance in a two-phase system containing two
largely immiscible solvents (water & octanol)
- Log10(P)
Improved Lipinski Parameters - correct answer ✔✔1. Partition coefficient Log(P) -0.4-5.6 range
2. Molar refractivity from 40-130
3. Molecular weight from 160-500
4. Number of atoms from 20-70
5. Polar surface area no greater than 140 A^2
CNS Drugs - correct answer ✔✔- need lower Polar Surface Area (A^2) to cross BBB
Modification of Proteins and/or nucleic acids - correct answer ✔✔- bad if unanticipated & non-selective
- good if selective
Esters, amide bonds, & disulfide bonds - correct answer ✔✔- labile in biological systems
- esters most labile
- useful for creating pro-drugs but can be broken down in-vivo
,Esters - correct answer ✔✔- most commonly bound pro-drug incorporate
- body is full of esterases capable of breaking down into active form
Easily druggable targets - correct answer ✔✔- enzymes - kinases, phosphatases, histone deacetylases
- cell surface receptors - GPCRs, RTKs, cytokine receptors
Undruggable targets - correct answer ✔✔- transcription factors
- scaffolding proteins
- protein-protein interactions involving large, flat protein-protein interfaces
Undruggable approaches - correct answer ✔✔- higher order complex formation (rapamycin, FK506,
cyclosporine) - chemobodies
- Synthetic lethality
- RNAi/Antisense RNA
- genome editing (CRISPR)
- SAR by NMR
ATP inhibitors - correct answer ✔✔- ATP-competitive inhibitors are easy to design
- kinases are present in nearly all signalling pathways
- ATP kinase binding sites are evolutionarily conserved
- high functional redundancy among kinases
Gatekeeper - correct answer ✔✔- defines size of specificity pocket
- bigger the keeper smaller the size of the specificity pocket
Specificity pocket - correct answer ✔✔- varies in size amonnst different ATP sites
, Gatekeeper makeup - correct answer ✔✔- predomenently methionine, threonine, luecine, or
phenylanalnine
ATP-competitive kinse inhibitors - correct answer ✔✔- recognize the active conformation of kinase (type
1)
Irreversible kinase inhibitors - correct answer ✔✔- covalently react with cysteine residues within the
kinase near the atp binding site
Kd - correct answer ✔✔- dissociation constant
- concentration of a ligand where half of the binding sites on a protein are bound
- circle size is proportional to binding affinity
Difficult to develop specific active site kinase inhibitors - correct answer ✔✔- due to gatekeeper
mutations
- active site mutations
- resistance over time
- overexpression of kinase
- functional redundancy
William Coley - correct answer ✔✔- father of cancer immunotherapy
- developed concoction mixture of killed bacteria that was injected intratumorally, causing cancer
regression
- results were hard to duplicate due to Coley's poor record taking skills
Cross-presentation of tumor antigens - correct answer ✔✔- APCs pick up tumor antigens and present to
dendritic cells
- dendritic cells present tumor antigens and co-stimulators to CD8+ cells and induce tumor-targeted
execution
Bone marrow transplant - correct answer ✔✔- form of cancer immunotherapy
