Molecules Med Chem Exam Flashcards
1
Q
Molecules with molecular weights of less than 900Da (prefer 500Da)
A
Small molecules
2
Q
Generally macromolecules such as proteins, antibodies, and vaccines
A
Biologics
3
Q
% of drugs that are biologics
A
27%
4
Q
How many drugs are approved each year?
A
Approx 32
5
Q
% of drugs that are small molecules
A
80-90%
6
Q
3 things that define that shape of a molecule
A
- Bonding/hybridization
- Stereochemistry
- Conformation
7
Q
If __________ isn’t the same on two molecules even if the shape is, they will probably not have the same effect on a target
A
Aromaticity
8
Q
Alkyl side chains
Isolated heteroatoms
Tetrahedral
A
Sp3
9
Q
Double bonds
Carbonyls
Heteroatoms NEXT to the double bonds are this hybridization
Planar
A
Sp2
10
Q
Triple bonds
Linear
A
Sp
11
Q
Do smaller or larger rings have more strain?
A
Smaller
12
Q
Bonds form via sharing electrons (most common)
A
Covalent interaction
13
Q
Don’t actually form a bond i.e. Van der Waals, H-bonds, Ionic interactions
A
Noncovalent Interactions
14
Q
Covalent bond where the electrons are NOT shared equally
A
Polar covalent bonding
15
Q
An atoms ability to pull electron density toward itself
A
Electronegativity
16
Q
Carbonyl-like groups
Halogens
Alcohols
Amines
Withdrawing or donating?
A
Withdrawing
17
Q
By resonance
Oxygen, sulfur, or nitrogen atom next to a double bond/aromatic system due to resonance
Must be Sp2!
Withdrawing or donating?
A
Donating
18
Q
Accept electrons
A
Electrophile
19
Q
Donates electrons
A
Nucleophile
20
Q
Why is fluorine NOT and electrophile? (doesn’t accept electrons)
A
It’s present in many drug molecules. Has significantly stronger bonding with carbon than other halogens
21
Q
Why are halogens, NOT fluorine, not good drug molecules?
A
Them accepting electrons from the nucleophile displaces good leaving groups to form new bonds. Easy reaction?
22
Q
Sulfates and phosphates increase _________
A
Water solubility
23
Q
Why are nitrogen atoms more electron donating to the carbonyl than oxygen atoms?
A
Because nitrogen atoms are less electronegative
24
Q
Movement of electrons through multiple bonds of a molecule
A
Resonance
25
If one of the lone pairs is able to line up with the pi system of the double bond, it will ____________ resonance stability
Increase
26
Fat-loving
Non-polar (alkanes)
Lipophilic
27
Water-loving
Polar groups i.e. OH, COOH, and amines
Hydrophilic
28
The tendency of non-polar substances to aggregate in solution OR bind to a protein
Hydrophobic effect
29
Interaction between 2 non-polar groups (drug and receptor)
Forces out water molecules and breaks up H-bonding
Hydrophobic interaction
30
Aromatic ring on top of another one
Pi stacking
31
Pi stacking with different electron densities
Charge transfer interaction
32
Non-identical mirror images
Enantiomers
33
R direction
Clockwise
34
S direction
Counterclockwise
35
A measured property for each individual molecule
Doesn't matter how many stereogenic centers are present of if they are R/S
ONLY matters how the molecule rotates plane polarized light
+/- (physical measurement)
36
Dextrorotatory
+
37
Levorotatory
-
38
For a molecule that has 3 points of contact with a target molecule, its enantiomer will have at most, only 2
Easson-Stedman Model
39
Is a single enantiomer always better?
No. One confirmation may go to the other and produce bad effects i.e. thalidamide
40
1.3kcal/mol ratio
10:1
41
2.6kcal/mol ratio
100:1
42
The _______ the energy, the more a molecule will exist in that conformation. (Does not always mean it is the most biologically active)
Lower
43
They do not have a role in the primary metabolism of the producing organism. No nutritional/structural function
Defensive
Possess desired chirality to exhibit biological activity
Secondary Metabolites
44
Natural products are meant to interact with _________ of growth/survival in organisms
Enzymes
45
The physical, chemical, biochemical, and biological properties of drugs, drug substances, or potential drugs and drug substances of natural origin, as well as the search for new drugs from natural sources
Pharmacognosy
46
% of drugs associated with natural products
50%
47
% of natural product cancer drugs
80%
48
% of natural product vaccines
21%
49
% of drugs that are synthetic
30%
50
Conversions of pure drug morphine
Codeine
Heroin
Methadone
Meperidine
Oxycodone
51
Conversions of pure drug Quinine (malaria)
Chloroquine
Mefloquine
52
Conversions of pure drug Taxol (cancer)
Taxotere
53
Conversions of pure drug lovastatin
Lipitor
Crestor
Pravastatin
Fluvastatin
Zocor
54
Natural products occupy a _____________ region of chemical space with synthetic compounds
Complementary
55
The relationship between man and his ambient vegetation. Medicinal uses of plants.
Ethnobotany
56
Increased biodiversity = Increased ___________
Chemical diversity
57
Regions containing a high percentage of endemic plant species that are threatened with destruction due to primary loss of vegetation
Biodiversity Hotspots
58
Profiling and screening of plant extracts for bioactive compounds with potential sources of new bio-based drugs
Bioassay guided fractionation
59
End up with multiple fractions containing compounds separated by polarity
Partition scheme
60
Newer technique to use versus partition scheme
Gene editing
61
4 types of biologics
Antibody-based
Vaccines
RNAi
Gene Therapy
62
Therapeutic genes packaged in a "delivery vehicle"
Viruses modified to carry human DNA
Cell makes new protein using new gene
Vector
63
Stem cell and bone marrow transplants are examples of _________
Cell therapies
64
Virus that permanently alters gene
Retrovirus
65
Virus where DNA is never integrated, retains epigenetic signature
Adenovirus
66
Immunity that is highly specific to a particular pathogen
Adaptive Immunity
67
Immunity that is just recognition of foreign particles
Innate Immunity
68
Natural passive immunity
Maternal
69
Natural active immunity
Infection
70
Artificial passive immunity
Antibody transfer
71
Artificial active immunity
Immunization
72
Antigen-presenting cells that digest most of the pathogen except antigens
Display antigens on their surface
Macrophages
73
White blood cells in the immune system
Lymphocytes
74
Cells that produce 100 million antibody proteins to combat foreign entities
B Cells
75
Cells that are cytotoxic, meaning they can kill infected cells
Stimulate and direct activity of B cells
T cells
76
Goal of vaccines is to...
Produce immunity effect (Lymphocytes, B cells, and T cells)
77
A live or inactivated substance capable of producing an immune response OR anything that can be bound by an antibody
Antigen
78
mRNA encoding for spike protein
mRNA/COVID-19 Vaccine
79
Glycoproteins that are produced by antibody-secreting B cells
Designed to recognize specific antigens through production from only one type of B cell
Antibodies
80
Antigen binding site
Paratope
81
Produced through hybridoma tech
2 different cell lines fused together
The immortalized cells provide survivability and ability to be reproduced in culture
Provide increased SPECIFICITY for antigen recognition over polyclonal varients
Monoclonal Antibodies
82
Monoclonal antibodies attached to biologically active drugs by chemical linkers with liable bonds
Facilitates the use of more toxic compounds
Antibody drug conjugates (ADCs)
83
Benefit of ADCs
Discriminated between healthy and diseased tissues, can eliminate diseased cells without harming the healthy cells
84
Substance that inserts itself into a cell and binds to its DNA
Intercalator
85
Calicheamicin
An intercalator where antibodies are not recognized/metabolized in the same way that drugs are based on size
Trojan horse for the drug to get into the cells undetected
86
3 Parts of PROTAC
1. Target-binding ligand
2. E3 ligase ligand
3. Linker
87
Advantages to traditional inhibitors
Catalytic activity
Complete removal of protein
88
Role of E3 ligase in PROTAC
To ubiquinate (alter) another protein via post translational modification
Can mark for degradation
89
What activates degradation in PROTAC?
Proteasome
90
How much drug reaches the blood supply and becomes available to target tissue
Bioavailability
91
What does a drug need to be able to do to get to the site of action?
Cross cell membranes and pass through blood supply
92
Challenges in the GI tract
pH changes
Encounters enzymes designed to hydrolyze large molecules
93
Does passive or active transport have structural specificity?
Active
94
Taking in molecules via surrounding by the membrane and formation of a vacuole
Endocytosis
95
Sending molecules out of cells
Efflux
96
Passing between cells
Paracellular
97
Physiochemical properties are dependent on a molecules' _____________
Functional groups
98
What compounds are much easier to purify and handle?
Crystalline
99
MP and crystalline relationship
The more crystalline (ordered), the higher the MP
100
Qualities of an ordered compound
High aromaticity
High planar
Low alkyl chains
Pi stacking
High IMF
101
3 ways to manipulate MPs
1. Salt formatin
2. Introduction of symmetry
3. Making derivatives with something that tends to crystallize i.e. phosphate derivative
102
Lipinski's Rule of 5
Solubility is key
Mol weight of < 500
LopP < 5
No more than 5 H bond donors
No more than 10 H bond acceptors
103
Lipinski's rule only works on which type of molecules?
Synthetic
104
Rule of 3
Scaled back Lipinski's rule
Mol weight < 300
Up to 3 H bond donors
Up to 3 H bond acceptors
LopP less than or equal to 3
105
Any single, non-ring bond attached to a non-terminal, non-hydrogen atom
Rotatable bond
106
What bond has high barrier to rotation?
C-N nitrile bond
107
A more rigid molecule will have _________ polar surface area and will not be as susceptible to promiscuous binding to metabolic enzymes or transporters
Lower
108
The __________ the # of rotatable bonds, the better oral bioavailability
Lower
109
Rigidity in relation to bioavailability
More rigid, higher bioavailability
110
If a compound is too ________ it may bind too strongly to plasma protein and free blood [ ] will be too low to produce good effect. Why?
Lipophilic; It will be distributed into the lipid bilayers and be unable to reach the inside of the cell
111
Lipophilicity in relation to excretion and metabolism
High lipophilicity = High metabolism and excretion
112
Measure of solubility; estimates how well a drug will pass through a biological system by stimulating membrane and blood
Partition coefficient
113
LogP in relation to water solubility
The smaller the LogP, the more water soluble the molecule is
114
Why do we want high lipophilicity?
High lipophilicity means that it will activate P450, which increases metabolism. Increased metabolism means increased clearance. This overall decreases the lipophilicity, which is good
115
Why do we want more heteroatoms for water solubility?
More heteroatoms means more opportunities to H bond, which increases polarity and water solubilty
116
LogP only works for __________ molecules
Neutral
117
Drugs are absorbed ___________ when they are un-ionized due to lipophilic membrane
Passively
118
The effective lipophilicity of a compound at a given pH, and is a function of both the lipophilicity of the un-ionized compound and the degree of ionization
LogD
119
If a compound can ionized, then the observed partitioning between water and octane will be _____ dependent
pH
120
Do salts have high or low water solubility?
High
121
A measure of stability of the deprotonated species
pKa
122
Only need to use if pKa is within 2 units of pH; otherwise can assume that it exists in only one of them
Henderson Hasselbauch Eqn
123
What kind of groups would increase drug solubility?
Groups that can be ionized (acids and amines) and introducing more heteroatoms capable of H bonding
124
Why are the ester and amide significantly LESS withdrawing than the aldehyde and ketone?
Because the heteroatoms in esters and amides donate electron density back into the carbonyl making it less withdrawing
125
Active site consists of hydrophobic substrate binding domain containing a heme prosthetic group
Radical mediated process with Fe intermediate
Binds O2 and substrate
CYP450
126
Most of the oxidations we cover in class are ________________
Hydroxylations
127
Drugs and other compounds that come from the outside (exogenous) that an organism encounters. Metabolism will eliminate the harmful/useless ones
Xenobiotics
128
Primary site of metabolism in the body
Liver
129
Denotes the site of radioactive label in a molecule, typically a weak B emitter
Radioactive atoms can be introduced through chemical synthesis or through feeding experiements for some NPs
Radiolabeling
130
2 tools to ID Metabolites
NMR
Mass spec
131
Involved in the metabolism of approx 50% of drugs
It's rate of transcription is increased by certain drugs
Mediated by PXR
Ability to accommodate a wide variety of substrates in active site
CYP3A4
132
What is CYP3A4 made of?
Erythromycin and ketoconazole
133
Resonance relationship to resistance
Higher resonance = stronger resistance to nucleophilic attack because it doesn't want to give up lone pairs
134
Omega P450 binding and benefit
Binds to terminal carbon and is less sterically hindered
135
Omega-1 P450 binding and benefit
Binds to least sterically hindered, non-terminal carbon, is more stable/less energetic
136
Why do N, O, and S dealkylation fall apart after hydroxylation?
It is unstable and can easily break apart
137
Do amides or esters hydrolyze slower and why?
Amides hydrolyze slower because they are resonance stabilized, meaning they want to hold on to their electrons more, making the process take longer
138
The linking of highly polar groups to a drug in order to facilitate excretion
Conjugation
139
Why is glucuronidation so prevalent?
UGT's are located along the ER of the liver and epithelial cells of the intestine. As such, it is situated near many CYP450s so more metabolism of them
