Unit 1 Flashcards
1
Q
Medicinal Chemistry
A
The branch of chemistry that discovers and designs new therapeutic compounds and develops them into new drugs
2
Q
Medicine
A
Any substance used to treat disease
3
Q
Drugs
A
- molecules used as medicines or as components in medicines to diagnose, mitigate, treat, or prevent diseases
- compounds that have a biological effect on biological systems
4
Q
Eastern Medicine
A
Holistic, focus on the whole health and largely herbalism
5
Q
Western Medicine
A
Reductive, identify active components and active sites for diseases
6
Q
Pharmacodynamics
A
- biochemical and physiological effects of a drug mechanism of action
“What the drug does to the body”
7
Q
Pharmacokinetics
A
- drug absorption, distribution, and elimination from the body
“What the body does to the drug”
8
Q
Potency
A
The measure of an amount of drug required to produce an effect to a given intensity (lower conc needed for better effect)
9
Q
Efficacy
A
The maximum effect that can be expected by a drug
10
Q
Selectivity
A
The ability of a drug to discriminate between 2 targets (receptors, cell types, tissues, etc.)
11
Q
Therapeutic Index (TI)
A
The dosage amount (range) that provides the best therapeutic effect with minimal side effects (toxic)
12
Q
The best drugs are… (5)
A
- potent
- effective
- selective
- good TI
- have specific targets
13
Q
Types of drug targets (3)
A
- proteins
- DNA/RNA
- lipids
14
Q
Drug targets should be… (6)
A
- relevant to the disease
- limited to the disease system
- “druggable”
- easily tested in bioassays
- low toxicity profile
- have promising intellectual property (IP) status
15
Q
“Druggable”
A
- easy to acces
- readily available
- available binding
- vascularized
16
Q
Bioassay
A
An analytical or biochemical test of the potency of a substance on a biological target or system
17
Q
H-Bond Donors
A
-hydroxy (-OH)
- primary amines
- amide nitrogen
18
Q
H-bond acceptors
A
- ketones/carboxy
- tertiary amines
- ethers
-hydroxy
19
Q
Intermolecular Forces (7)
A
- covalent
- ionic (electrostatic)
- ion-dipole/dipole-dipole
- hydrogen bonds
- charge transfer
- London dispersion forces
- hydrophobic
20
Q
Effect of Cooperativity
A
Several weak interactions combine to produce strong interactions
21
Q
Major types of receptors (4)
A
- Ligand-gated ion channels
- G-protein coupled receptors
- Receptor Tyrosine Kinases
- In trace lunar Receptors
22
Q
Autocoids
A
A ligand that originates from inside the body and is considered a receptors’ “natural” ligand
Ex: insulin for the insulin receptor
23
Q
Xenobiotics
A
A ligand that originates outside the body and binds to a receptor (typically a drug, but can also be toxins, contaminants, etc,.)
Ex: synthetic insulin
24
Q
Agonists
A
Xenobiotics that can bind to the receptor and activate its normal function
25
Inverse Agonists
Xenobiotics that can bind to the receptor and activate an opposite function than the natural ligand
26
Antagonists
Xenobiotics that bind to the receptor and blocks the receptor from performing its normal function (inhibit activation)
27
Theories of Receptor-Drug Binding(6)
- occupancy theory
- rate theory
- induced fit
- macromolecular perturbation
- activation-aggregation
- two-state model
28
Induced fit theory
- the receptor is dynamic
- the receptor undergoes conformational changes while forming the ligand-receptor complex
- this conformational change optimizes binding interface with the ligand through intramolecular forces
29
Two-state Model
The receptor is dynamic and in equilibrium between active and resting states (active state initiates biological response)
Equilibrium without ligand = the basal state
30
Kd
Dissociation constant = affinity of the drug for the receptor
[substrate] @ 50% activity on dose-response curve
Kd Inc, Affinity Dec… Kd Dec, Affinity Inc.
31
Partial Inverse Agonist
Partial Opposite Response
32
Enzymes have 2 kinds of specificity:
1. Binding
2. Reaction
33
Binding Specificity
Enzymes may bind very specific substrates or broad substrates
(Either very specific with what it binds to or not very specific at all)
34
Reaction Specificity
Depends on the specific functional groups (amino acids) present in active site
35
Kcat (Catalytic Constant)
The number of substrates changed to product per second
36
Mechanisms of Enzyme Catalysis (6)
1. Approximation
2. Covalent
3. Acid/Base
4. Electrostatic
5. Desolvation
6. Strain/distortion
37
Approximation
- Rate acceleration via proximity, how close they are
- Enzyme-substrate are positioned close and in preferred geometry
38
Covalent Catalysis
Enzymes covalently bind to substrates and can act as leaving group
39
Two Kinds of Acid/Base Catalysis
1. Specific
2. General
40
Specific Acid/Base Catalysis
Determined by [H3O+] or [OH-] (pH)
41
General Acid/Base Catalysis
Determined by increase in [Buffer] at constant pH
42
Electrostatic Catalysis and Desolvation
- enzymes stabilize intermediates or destabilize ground states
- desolvation (removal of water) can destabilize ground states promote electrostatic catalysis
43
Strain or Distortion Catalysis
- Strained molecules are more reactive
- the more an enzyme distorts the substrate, the faster the rate of the reaction
44
Cofactors
Non-protein molecules that are required for enzyme catalysis and are broken down into two categories
45
Coenzyme
Small organic molecules that loosely bind or fit into an active site to assist in catalysis and are often derived from vitamins
46
Reversible Inhibition
Inhibition of the enzyme is temporary, and the interactions are not covalent
(Competitive for the active site)
47
Irreversible inhibition
Inhibition of the enzyme is permanent and enzyme cannon regain activity, usually involves covalent interactions
48
Why does dosing matter?
Inhibition depends on Ki and Km
- Drugs are given in regular does to increase the amount of inhibitor, increasing the E-I complexes present, which increases the effects of the drug administered
49
IC50 Value
- concentration that produces 50% enzyme inhibition
- must be measured under constant enzyme and substrate concentrations
- can be used to compare inhibitors agains the same enzyme at the same concentration
50
Approaches to Designing Reversible Inhibitors(4)
1. Simple Competitive Inhibition
2. Alternative Substrate Inhibition
3. Transition State Analogue Inhibition
4. Slow Tight Binding Inhibition
51
Simple Competitive Inhibition
- bind quickly and reversibly
- inhibitors tend to have similar structure to natural substrate or product of enzyme
- usually start with structure of substrate
52
Alternative Substrate Inhibition
- occurs when an inhibitor can also act as a substrate for the enzyme
- block the “true substrate” from binding and being converted to the product
- often is similar to the structure of the substrate
53
Antimetabolites
Drugs that are chemically similar to necessary metabolites (purines, pyrimidines, folate) and interfere in biosynthesis of that metabolite
54
Prodrugs
Start as an inert compound but get metabolized into an active form (pharmacokinetics)
55
Transition State Analogue Inhibition
- Enzymes bind to substrates tightest at the transition state of a reaction
- a drug that mimics the transition state, would bind more tightly to the enzyme than the substrate
- need to know mechanism
56
Slow Tight Binding Inhibition
- reach equilibrium between enzyme and inhibitor slowly
(Kon = small; Koff = small)
- unknown causes
57
Competitive Inhibition
Substrate and Inhibitor compete for the same active site - affect slope of the plot
58
Uncompetitive Inibition
Inhibitor only binds the enzyme/substrate complex (only effective at high substrate concentrations) - affects only y-intercept of plot
59
Noncompetitive Inhibition
Inhibitor can bind to both the enzyme and enzyme/substrate complex - affects both slope and y-intercept (AKA mixed inhibitor)
60
Irreversible Inhibitors
Enzyme and inhibitor are bound covalently and permanently - no Koff
61
Irreversible Inhibitors (types (2))
1. Affinity Labeling Agents
2. Mechanism-based enzyme inactivators
62
Affinity Labeling Agents
- contain reactive electrophile groups
- tend to be less selective and more toxic
- covalently bind to nucleophiles in the active site
63
Mechanism-based enzyme inactivators
- may not have reactive groups that are immediately noticeable
- are more selective and less toxic
- modified by the enzyme into an active form that binds to active site
64
Difficulties of using DNA as Drug Targets
- everything has DNA, so specificity is difficult
- have to inhibit replication usually
- unknown effects of altering or changing DNA
- usually target for anti cancer drugs and antibiotics
65
DNA Structure for Druggability
Has major and minor groove and human DNA is packaged in chromosomes
- major groove = binding target for proteins
- minor groove = binding target for drugs
- chromosomes packed so tight, more difficult to access
66
Reversible Binders
Same interactions as reversible inhibitors in receptors and enzymes where they reversibly interact with the DNA
- bind by electrostatic interactions, groove binders, and intercalators
67
Alkylators
React covalently with DNA bases like irreversible inhibitors
68
Strand Breakers
Generative reactive radicals that cleave polynucleotide strands (especially toxic)
69
Minor Groove Binders
- targeted by drugs and small molecules
- specifically wants A-T rich regions
- displaces water along the groove and widens the groove
70
Intercalators
- aromatic and flat
- insert between DNA bases
- does NOT interrupt hydrogen binding
- causes DNA distortion
71
Bisintercalators
- bind two strands of DNA
- greater affinity for DNA
72
Alkylators
- electrophilic group irreversibly binds with target (DNA bases)
- occurs through intramolecular reaction and causes DNA strand cross linking
- can be caused by scission
- initially unreactive, becomes active when interacts with enzyme
73
Difficulties of Lipids as Drug Targets
- hydrophobic, not soluble if taken as a pill
- minimal receptor activity
- no charge, difficult targets
74
2 Hypotheses for Polyene mechanism of action
1. Ergosterol sponge
2. Ergosterol binding and pore formation
75
Penicillin
The miracle drug, targets material that only bacteria possess
76
Two Hypotheses for DNA strand breaking
- reduction of anthracycline core leads to hydroxyl radical
- iron complexed anthracycline can undergo Fenton reaction to form hydroxyl radicals
