Medicinal Chemistry T2 Flashcards
1
Q
DNA
A
Has four nucleic acid bases: Adenine, Guanine, Cytosine, Thymine
- Bind to deoxyribose sugar to form nucleosides
- Has 3 structures
2
Q
DNA: primary structure
A
Nucleosides are joined together by the enzyme DNA polymerase which forms the sugar phosphate bond.
3
Q
DNA: secondary structure
A
- two complementary DNA chains bind forming a double helix
- sugar phosphate is ionized and faces outward (favors H2O)
- nucleic acid base point inward and pair up to keep a helix diameter
- base pairs AT CG are stacked with van der wall interaction btwn pairs
4
Q
Base pairing
A
GC involves 3H bonds
AT involves 2H bonds
5
Q
DNA: tertiary structure
A
Supercoiling- topoisomerase enzyme help Double helix coils into 3D shape
6
Q
Topoisomerase enzyme
A
Passes sections of DNA through other sections of DNA by temporarily cutting and resealing the stands
- topoI1 cuts and reseals one DNA strand topoI2 does both
- uses the OH group in tyrosine residues to attack and cleave the PO4 group in DNA and is responsible for uncoiling DNA
- quinolone stabilizes the complex formed btwn bacteria DNA and related topoI enzyme in bacteria
7
Q
DNA Replication
A
- Strands separate and is copied by DNA polymerase
- nucleosides are added to the growing chain through a substitution RXN on the PO4 group
8
Q
Genetic polymorphism
A
Individual DNA differs average rate of 1/1000 DNA base pairs. Leads to small differences in proteins/receptors/enzymes btwn individuals.
9
Q
Personalize medicine
A
Genetic differences btwn individuals are exploited to predict and prevent disease before it happens as well as to make more effective drug therapies.
10
Q
RNA: primary structure
A
Similar structure to DNA
Ribose is the backbone sugar
Uracil used rather than thiamine
11
Q
RNA: secondary structure
A
Mostly single stranded
Some regions of helical structure because of base pairing within the same stands AU CG
12
Q
mRNA
A
Relays the code for a protein from DNA to the protein production site
13
Q
tRNA
A
The adapter unit linking the triplet code on mRNA to specific amino acid
14
Q
rRNA
A
Present in ribosomes (the production site for protein synthesis). Important both structurally and catalytically
15
Q
Transcription
A
The copying of a segment of DNA (gene) which codes for a specific protein
Made in nucleus, mRNA travels to ribosome in cytoplasm and rRNA /enzymes catalyze protein synthesize but each new amino acid is brought in by tRNA
16
Q
Translation
A
Process of protein synthesis
17
Q
Recombinant DNA technology
A
Injects specific genes into fast growing cells such as bacteria to produce large quantities of desired protein
- Human genes are split unevenly with sticky ends by restriction enzymes that recognizes specific base pair regions
- Lipase enzyme repai the chains by matching complimentary bases pairs from different strands
18
Q
Amplification of a gene
A
Uses two common vectors for introducing human DNA to bacterial cells
- Ex:Plasmids and bacteriophages
- specific genes can be inserted into a plasmid or bacteriophage by using restriction enzymes
- then plasmids or bacteriophage are introduced to bacterial cells to produce large quantities of desired protein.
19
Q
Plasmids
A
Circular segments of DNA that are naturally shared between bacterial cells
20
Q
Bacteriophages
A
Viruses that infect bacterial cells
21
Q
Application of genetic engineering
A
- Used to Harvest important proteins:insulin, human growth factor, monoclonal antibodies
- study of the molecular mechanism of target proteins (identification of crucial amino acids for enzymatic activity or binding) by synthesizing proteins with specific mutations
22
Q
Proteomics
A
Identification of the structure and function of new proteins
23
Q
Somatic gene therapy
A
Insertion of specific genes into humans that lack or have a defective gene through the use of a viral or non viral delivery system (caged molecule or polymer)
24
Q
Receptors
A
globular protein located mostly in the cell membrane, it recognizes messages coming from other cells
25
Signal Transduction
receptors transmit a message into the cell leading to a cellular effect
26
Structure and function of receptors
- binding result in an induced fit of the receptor protein to maximize intermolecular forces and lead to signal transduction.
- diff receptors=diff messengers
- each cell has a range of receptor in the cell membrane making it responsive to diff chem messengers.
27
Chemical messengers
come through either nerve cell or the circulatory system
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Neurotransmitter
chemicals removed from nerve endings that travel through the synapse to bind to receptors on target cells, short lived and responsible for messages between individual cells
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Hormones
Chem signal released from cells or glands that travel through the circulatory system to bind with receptors on target cells all over the body
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Examples of chemical signals
- epinephrine
- dopamine
- histamine
- serotonin
- ACH
- GABA
- ACE
- glutamic acid
- estradiol
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Rules of Chem signals
- many of them are polar except for estradiol which cant cross the cell membrane and interact with membrane bound receptors
- compounds with less than a 4:1 C: O+N ratio are water soluble
32
Receptor superfamilies
* ion channel-membrane bound- msecs
* G-protein coupled-membrane-seconds
* kinase linked-membrane-minutes
* intracellular-hours
33
Ion channel receptors
- part of an ion channel protein 5 subunit complex
| - hydrophillic chanels specific for Na, K, Ca, Cl ions
34
Ion Chanel mechanism
1. receptor binds a messenger leading to an induced fi a process called gating which opens the closed ion chanel
2. ions flow across the cell membrane into or out of the cell down the concentration gradient
3. Ion channels control the polarization and depolarization of nerve cells depending on the neurotransmitter.
35
Resting state of nerve cells
polarization- K ions are allowed to flow out of the nerve cell
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ACH binding
Na ions are allowed into the nerve cells to depolarize them and send a nerve signal as several Na ion channels open down the length of the nerve cells one at a time
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GABA or glycine binding
Cl ions are allowed to flow into nerve cell to polarize them (stop the signal)
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Ca ions
once the signal reaches the end of the nerve cell CA ions are allowed to flow un which lead to the release of a neurotransmitter into the synapse
39
Ion channel structure
- Each ion channel sub-unit has 4 trans-membrane that are hydrophobic with the TM2 of each protein sub-unit lining the central pore
- after the messenger bind to the receptor the TM2 segment of each sub-unit rotate to open the central pore
40
G-protein coupled receptors Mechanism
1. receptor binds a messenger leading to an induced fit
2. opens a binding site for the signal G-protein (made up of three sub-units) which is found in the membrane
3. G-protein binds to neucleotide GTP which weakens and lead to the breaking of the links between protein sub-unit.
4. subunit activate membrane bound enzymes by binding to allosteric binding ite
5. induced fit result in opening of the enzyme active site
6. Intracellular reaction is catalyzed which propagates the chem signal through 2ndary messengers.
41
G protein structure
- single unit protein with 7 TM regions
| - 30% of drugs interact with G-protein coupled receptors
42
Examples of G-protein recptors
- monoamines (dopamine, histamine,adrenaline,serotonin,ACH (muscarinic receptoronly))
- Opioids(morphine, codeine,enkephallinsendorphins)
- proteinhormones (ACE)
- Glutamate
- Ca+2
43
Kinase Linked Receptors
- bifunctional protein: receptor/enzyme
- activated by peptide hormones such as growth factors and cytokines
- overexpression of kinase receptors/kinases/growth factors result in cancer
- most protein kinase inhibitors inhibits ATP binding site than the substrate binding site
44
Growth factors
chemical messengers that stimulate cell growth and differentiation
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Cytokines
immunomodulating chemical meesengers
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Kinase Linked receptor mechanism
1. induced fit opens active site
2. Phosphorylation of protein substrate catalyzes within the cell
3. phosphorylation converts H bonding OH group into a negatively charge PO4 group whic forms ionic bonds with positively charged residues
- phosphorylation leads to change in enzyme structure which opens (or closes) active sites
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Kinase linked receptor structure
extracellular N terminal cahin
hydrophobic TM region alpha helix
intracellular C terminus
48
Kinase Linked receptor example
Tyrosine Kinase receptor: PO4late tyrosine residues on proteins
- Serine Threonine kinases- important in activating 2ndary messengers within the cell. Phosphorylate OH groups on serine or threonine residues
- imatinib -inhibits the Abelson or Ber-Abl tyrosine kinase receptor used to treat Philadelphia Chromosome positive Chronic Myelogenous Leukemia
49
kinase Linked Receptor other example
* Epidermal growth factor EGFR (tyrosine kinase)
- EGF b inds 2 tyrosine kinase receptors which leads to the auto-phosphorylation of each half of the EGF-R by the other half
- auto phosphorylation of the EGF-R acticates the receptor to catalyse reactions which activate 2ndary messengers
* insulin receptor (tyrosine kinase)
- tetrametric complex
50
Intracellular Receptors
chem messengers must cross the cell membrane so messenger must be hydrophobic
-examples are sterois like estrogen
51
Intracellular receptor mechanism
1. chem signal bind to receptor inside of the cell the receptor dimerizes and bind to co-receptor protein.
2. complex then binds to a region of DNa witha specific sequence
3. transcription is switched on or off which inhibits or activates protein synthesis
52
Intracellular receptor structure
contains zinc finfer region that has a 9 Cys residues that bind two zinc ions to stabilize the protein;s binding to DNA
53
Agonist
drugs that mimic the action of the natural chemical messenger and activate the receptor
54
Agonist structure
- must have the correct binding groups that is correctly positioned to interact with complementary binding receptors
- drug must have correct shape to fit binding site
55
Agonist example: Albuterol
salbutamol (albuterol)
- agonist of the beta-adrenorecptor ( G-proteinc coupled recptor)
- binds to the beta2-receptors in the lungs over the beta1-receptors in the heart to treat asthma
- longer acting than epinephrine since it isnt metabolized by the enzyme catechol-O-methyl transferase (COMT)
56
Agonist example: Morphine
- agonist of the endogenoeuous peptided me-enkephalin (tyr-gly-gly-phe-Met), leu-enkephalin (tyr-Gly-Gly-Phe-Leu), endorphins, and dynorphins
- -opioid peptides contain terminal tyrosine group which binds to opioid receptors (G-protein coupled)
57
Opioid receptor: Mu
high activity with morphine, low with Enkephalins, high endorphins, medium Dynorphins
-strongest analgesic effect, but causes respiratory depression,euphoria,sedation and addiction
58
Opioid receptor: Kappa
low activity with morphine, none with Enkephalins, high endorphins, high Dynorphins
- weaker analgesic effect, but no respiratory depression,euphoria,or addiction.
- considered safest opioid receptor
59
Opioid receptor: Delta
low activity with morphine, high with Enkephalins, high endorphins, low Dynorphins
-weak analgesic effect, some respiratory depression but no euphoria,sedation or addiction.
60
Agonist example: Pilocarpine
obtained from the shrubs of pilocarpus, is a muscarinic Ach receptor agonist
-used to contract the iris sphincter muscle and treat glaucoma (fluid pressure due to optical nerve damage)
61
Allosteric Agonist
agents that enhence receptor activity by binding to an allosteric binding site rather than the messenger binding site
62
Allosteric Agonist example: Benzodiazepines
- Valium targets the allosteric site of GABAa receptor to treat anxiety and insomnia
- increases the binding of GABA resulting in a calming effect
63
Side note on GABA
the GABAa receptoe (ion channel receptor) causes CL- ions to flow into nerve cells to polarize them (stop the nerve signal)
64
Antagonist
Drugs that inhibit the action of the natural chemical messenger and block the receptor
65
Antagonist structure
- binds to the active site but fail to produce an induced fit (maybe it isnt using all the binding regions of the active site) so receptor is not activated
- forms binding interactions with binding regions in the site not used by the natural messenger to produce a different induced fit = receptor not activated
- most act through reversible intermolecular interactions at the active site
66
Antagonist example: Cimetidine
-histamine H2 receptor that blocks gastrc acid releasse and its used to treat peptic ulcers
67
Antagonist example: Pactocol and atenolol
beta1-adrenoceptor antagonist (g-protein coupled) in the heart
- used to treat angina
68
Antagonist example: tubocurarine and suzamethonium
antagonize the nicotinc ACh receptor (ion channel)
- used in general anesthesia
extra ammonium group probably binds another anionic binding region
69
Antagonist example: Raloxifene
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estrogen receptor (intracellular receptor responsible for breast cell growth) antagonist
-used to treat breast cancer
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70
Desensitization
cell/body becomes less responsive to chem. messenger due to prolonged binding of agonist to a receptor
- prolonged binding of agonist leads to PO4lation oh hydroxyl or phenol groups in the receptor which then changes its shape and is inactivated
- dePO4lation occurs once agonist departs and returns to normal state
71
Desentization consequences
- long term binding of agonist lead to reduction in the numbers of receptors available.
- removal of drug/receptor complex from cell and or reduction in the synthesis of receptors (cell stop making that receptor)
72
Sensitization
cell/body becomes more responsive to chem messenger due to prolonged binding of antagonist to a receptor
73
Sensitization consequences
- long term binding of antagonist can lead to increase in the synthesis of receptors which can lead to tolerance (increase dose of antagonist required to achieve same effect)
- removal of antagonist after sensitization results in supersentitivity to normal levels of chem mess. due to the excess receptors
- may cause withdrawal symptoms and dependence/ addiction until excess receptors are removed
74
receptor types and Subtypes
- chemical messengers bind to different types/ subtypes of receptors
- diff organs have a preference for some types or subtypes of receptors which allows for drug action selectivity
75
Drugs acting on DNa
1. Intercalating agents
2. Topoisomerase poisons
3. Alkylating agents
4. Metallating agents
5. Chain cutters
6. Chain terminators
- all usually treat cancers and bacterial/viral infections
- tend to be toxic and lead to cancer
76
Intercalating Drugs
- contain planar aromati/hetoaromatic ring systems that slide btwn aromatic rings of adjacent base pairs
- some contain positibely charged groups that also bind to PO4 on DNA
- may prefer major or minor groove to disrupt helix shape
- intercalation prevent replication and transcription and inhibit topoisomerase
77
Intercalatin Drugs example: antibacterial/antimalarial
- aminocridines: protonated at phisiological pH allowing for an additional interaction with phosphate group in DNA
- Quinnine and chloroquinine (antimalerial)
78
Intercalating Drugs example: antibacterial/antimalarial
- dactinomycin: contains pentapepide that can additionally H-bond to guanine bases and prevent unwinding of the helix
- doxorubicin: contains charged amino group that can interact wth phosphate group in DNA
79
Chain Cutters
- most intercalate DNA first
- abstact H from DNA to generate radicals
- Radicals react with O to form peroxy intermediates that results in DNA chain fragmentation
80
Chain cutter example: bleomycin
- N on primary amine, pyrimidinee ring, and imidazole rings bind to Fe2+ which is oxized to Fe3+ by fromin super oxide and hydroxyl radicals that damage DNA
- also inhibits DNA ligase enzyme (repairs DNA)
81
Chain Cutter example: Calicheamicin y1
- anticancer
- binds to minor groove of DNA through its sugar and the enediyne system undergoes bergman rearangement to generate a diradical which removes 2 H from DNA resulting in chain cutting
- Ring closing through Micheal reaction 10-membered strained ring containing an enediyne and allows bergman cyclization to occur at room temp (req high T)
82
Topoisomerase Poisons
- non intercalating
| - stabilize the complex btwn DNA and topoisomerase II enzymes (dont inhibits these enzymes directly)
83
Topoisomerase Poisons: Podophyllotoxins
- etoposide and teniposide are Topoisomerase II poisons
- phodophyllotoxins with a phenol group at the 4' position also cause a H atom abstraction from DNA through a free radical mechanism that leads to DNA strand fragmentation
84
TopoIsomerase poisons example: camptothecin
- and analogues like topotecan and irinotecan stablelize the dna-topoIsomerase 1 complex
- quinolones and fluoroquinolones such as nalixidic acid and ciprofloxacin stabilize the complex formed between DNA and the bacterial topoisomerase enzyme
85
Alkylating agents
- contain highly electrophillic groups (good leaving groups)
- forms covalent bonds to nucleophilic groups in DNA (n7 of gua)
- toxic side effects
- prevents replication and transcription
- if they contain two electrophillic groups they can interstrand and interstrand cross linking
- mask portions of DNA or misplacing of DNA bases
86
Alkylating agent examples: chlormethine
Nitrogen mustard compound cause interstrand cross-linking by alkylating guanines
-anticancer
87
Alkylating agent examples: others
- alkyl sulfonates like busulfan anti cancer cause interstrand cross linking between guanines
- oxamniquine (anti-schistosomiasis) is activated into a DNA alkylating agent by an sulfotransferase enzyme found in schistosomal flatworms
88
Alkylating agent examples: others
- Dacarbazine: anti cancer is oxidized by cytochrome p450 enzymes in the liver and degrades to generate the methyldiazonium upon which methylates n7 of guanines
- mitomycin C: anti cancer is converted in the body to an interstrand alkylating agent that reacts with guanines
89
Metallating agents example: cisplatin
- cis-dichloroplatinum (II) compound
- neutral inactive molecules that are activated inside of the cells by low [Cl]
- Cl substituents replaced by H2O forming positively charged metal
- metal reacts with N7 of two adjacent guanines to form intrastrand cross linking
90
Chain terminators
- Similar to natural nucleosides
- Must be able to H-bond to a nucleic acid base on the template strand and must have triphosphate group
- they are added to a growing DNA chain by DNA polymerase and inhibit chain growth
91
Chain terminator example: azidothymidine AZT
- antiviral treat HIV
- phosphorylation to a triphosphate in the body
- AZT 3PO4 is added to growing chain of DNA and act as a terminator. It inhibits the viral reverse transcriptase
92
Chain terminator example: Acyclovir
- Antiviral for herpes simplex
- phosphorylated to a tri-phosphate in the body
- tri-phosphate is added to growing chain of DNA and act as a terminator. It inhibits the viral DNA polymerase
93
Reversible inhibitors
-drug binds reversibly to the active site of the enzyme through intermolecular interactions.
94
Competitive inhibitors
Drug is competing with the natural substrate for the active site, therefore the inhibition is reversed if substrate concentration increases or drug concentration decreases.
95
Reversible inhibitor
- similar in structure to substrate, product or cofactor , has right structure to allow binding to active site
- substrate or cofactor blocked from active site
- doesn't under go reaction
96
How to increase inhibition?
Increase concentration of drug or designing an analogue with stronger binding interactions
97
Competitive inhibitor ex: sulfonamides
- inhibit dihydropteroate synthetase by blocking natural substrate from binding
- stop biosynthesis of tetrahydrofolic acid
98
Competitive inhibitor examples
- kinase inhibitors such as imatinib
- ACE inhibitor such as enalaprilat
- statins such as lovastatin
- viral protease inhibitors such as saquinavair
99
Transition state inhibitory
Designed to mimic the transition state of enzyme catalyzed reaction
100
Transition state inhibitor
- typically bind using intermolecular interactions but more strongly than drugs mimicking substrate or product
- high energy, transient species & can't be isolated or synthesized
- mimics stereochemistry and binding properties of reaction intermediate but stable
101
Transition state inhibitor ex: aliskiren
- renin inhibitor
- block synthesis of angiotensin I & II
- act as anti hypertensives
- contains two aspartyl bridging a water molecule in active state that cleave peptide bonds
102
Transition state inhibitor ex: saquinavair
- inhibit HIV protease enzyme
| - used to treat AIDs
103
Transition state inhibitor ex: enalaprilat
- inhibit ACE which converts decapetide angiotensin I into octapeptide angiotensin II
- lowers blood pressure
- Zn2+ ion binds and activates the carbonyl in angiotensin I for hydrolysis
104
Transition state inhibitor ex: statins
- inhibit HMG-CoA reductase
| - block biosynthesis of cholesterol by inhibiting conversion of HMG-CoA into mevalonate (precursor of cholesterol)
105
Irreversible inhibitor
Drug binds irreversibly to active site of enzyme through covalent bond
- substrate permanently blocked from active site & increasing substrate concentration doesn't reverse inhibition
106
Irreversible inhibitors : penicillin & cephalosporins
- inhibit transpeptidase enzyme (serine) , which is responsible for cross-linking the peptide side chains
- results in compromised cell wall that doesn't prevent cell bursting
- react with serine in active site of transpeptidase enzyme
107
Irreversible inhibitor ex: orlistat
- anti-obesity drug
| - inhibit serine in active site of pancreatic lipase thus preventing disgestion of triglycerides
108
Irreversible inhibitor ex: disulfiram
- anti-alcoholism drug
- inhibits cysteine , converting acetaldehyde to acetic aid
- prevents normal metabolism of ethanol and instead leads to build up of acetaldehyde (severe feeling of hangover within minutes)
109
Irreversible inhibitor ex: omeprazole
- anti ulcer drug
- inhibits cysteine in proton pump enzyme
- prevents pumping of protons into stomach
- only active in highly acidic environment
110
Suicide substrate
- drugs which are converted to irreversible inhibitors by enzyme catalyzed reaction
- react with target enzyme once formed
- more selective than other irreversible inhibitors since they react on-site with enzyme that made it
111
Suicide substrate Ex: 5-fluorouracil
- used to treat cancer
- dUMP is converted in body to nucleoside of thymidine
- first converted to FdUMP as it picked up a deoxyribose sugar and phosphate group
- then inhibits cysteine in active site of thymidylate synthase
112
Comparison of inhibitors
IC50 = concentration of inhibitor required to reduce the activity of an enzyme by 50%
112
Allosteric inhibitors
- inhibitor binds reversibly or irreversibly to allosteric site of enzyme
- induced fit alters active site shape & not recognized by substrate
- few allosteric inhibitors have been designed
