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GMS 6504 Exam With Questions And Accurate Answers
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GMS 6504 Exam With Questions And AccurateAnswers 2024-2025
Lipinski's rule of 5
- Poor absorption or permeation are more likely when:
1. mass > 500 Da
2. highly lipophilic - logP > 5
3. > 5 H bond donors
4. > 10 H-bond acceptors
Partition coefficient
p = C(octanol)/C(water)
- ratio of the equilibrium conc. of dissolved substance in a two-phase system consisting
of two largely immiscible solvents (water & octanol)
- Log10(P)
Optimized Lipinski Parameters
1. Log(P) partition coefficient -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
- must have lower Polar Surface Area (A^2) to cross BBB
Modification of Proteins and/or nucleic acids
- bad if unanticipated & non-selective
- good if selective
Esters, amide bonds, & disulfide bonds
,- labile in biological systems
- esters most labile
- useful to create pro-drugs but can be cleaved in-vivo
Esters
- most common bound pro-drug incorporate
- body full of esterases capable of cleaving to active form
Easily druggable targets
- enzymes - kinases, phosphatases, histone deacetylases
- cell surface receptors - GPCRs, RTKs, cytokine receptors
Undruggable targets
- transcription factors
- scaffolding proteins
- protein-protein interactions with large, flat protein-protein interfaces
Undruggable approaches
- higher order complex formation (rapamycin, FK506, cyclosporine) - chemobodies
- Synthetic lethality
- RNAi/Antisense RNA
- genome editing (CRISPR)
- SAR by NMR
ATP inhibitors
- 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
- defines size of specificity pocket
, - bigger the keeper smaller the size of the specificity pocket
Specificity pocket
- varies in size amonnst different ATP sites
Gatekeeper makeup
- predomenently methionine, threonine, luecine, or phenylanalnine
ATP-competitive kinse inhibitors
- recognize the active conformation of kinase (type 1)
Irreversible kinase inhibitors
- covalently react with cysteine residues within the kinase near the atp binding site
Kd
- 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 design selective active site kinase inhibitors
- because of gatekeeper mutations
- active site mutations
- resistance over time
- overexpression of kinase
-functional redundancy
William Coley
- father of cancer immunotherapy
- concocted mixture of killed bacteria; mixture was injected intratumorally and resulted in
tumor regression
- mixture's success was difficult to reproduce since Coley was a poor record keeper
Cross presentation of Tumor Antigens
- APCs take up tumor antigens and present to dendritic cells
- dendritic cells present tumor antigens with co-stimulators to the CD8+ cell and induces
tumor targeted execution
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