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Medicinal Chemistry > Unit 1 > Flashcards

Unit 1 Flashcards

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1
Q

Medicinal Chemistry

A

The branch of chemistry that discovers and designs new therapeutic compounds and develops them into new drugs

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2
Q

Medicine

A

Any substance used to treat disease

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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
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4
Q

Eastern Medicine

A

Holistic, focus on the whole health and largely herbalism

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5
Q

Western Medicine

A

Reductive, identify active components and active sites for diseases

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6
Q

Pharmacodynamics

A
  • biochemical and physiological effects of a drug mechanism of action
    “What the drug does to the body”
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7
Q

Pharmacokinetics

A
  • drug absorption, distribution, and elimination from the body
    “What the body does to the drug”
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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)

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9
Q

Efficacy

A

The maximum effect that can be expected by a drug

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10
Q

Selectivity

A

The ability of a drug to discriminate between 2 targets (receptors, cell types, tissues, etc.)

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11
Q

Therapeutic Index (TI)

A

The dosage amount (range) that provides the best therapeutic effect with minimal side effects (toxic)

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12
Q

The best drugs are… (5)

A
  • potent
  • effective
  • selective
  • good TI
  • have specific targets
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13
Q

Types of drug targets (3)

A
  • proteins
  • DNA/RNA
  • lipids
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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
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15
Q

“Druggable”

A
  • easy to acces
  • readily available
  • available binding
  • vascularized
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16
Q

Bioassay

A

An analytical or biochemical test of the potency of a substance on a biological target or system

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17
Q

H-Bond Donors

A

-hydroxy (-OH)
- primary amines
- amide nitrogen

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18
Q

H-bond acceptors

A
  • ketones/carboxy
  • tertiary amines
  • ethers
    -hydroxy
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19
Q

Intermolecular Forces (7)

A
  • covalent
  • ionic (electrostatic)
  • ion-dipole/dipole-dipole
  • hydrogen bonds
  • charge transfer
  • London dispersion forces
  • hydrophobic
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20
Q

Effect of Cooperativity

A

Several weak interactions combine to produce strong interactions

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21
Q

Major types of receptors (4)

A
  1. Ligand-gated ion channels
  2. G-protein coupled receptors
  3. Receptor Tyrosine Kinases
  4. In trace lunar Receptors
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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

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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

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24
Q

Agonists

A

Xenobiotics that can bind to the receptor and activate its normal function

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25
Q

Inverse Agonists

A

Xenobiotics that can bind to the receptor and activate an opposite function than the natural ligand

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26
Q

Antagonists

A

Xenobiotics that bind to the receptor and blocks the receptor from performing its normal function (inhibit activation)

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27
Q

Theories of Receptor-Drug Binding(6)

A
  • occupancy theory
  • rate theory
  • induced fit
  • macromolecular perturbation
  • activation-aggregation
  • two-state model
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28
Q

Induced fit theory

A
  • 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
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29
Q

Two-state Model

A

The receptor is dynamic and in equilibrium between active and resting states (active state initiates biological response)
Equilibrium without ligand = the basal state

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30
Q

Kd

A

Dissociation constant = affinity of the drug for the receptor
[substrate] @ 50% activity on dose-response curve
Kd Inc, Affinity Dec… Kd Dec, Affinity Inc.

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31
Q

Partial Inverse Agonist

A

Partial Opposite Response

32
Q

Enzymes have 2 kinds of specificity:

A
  1. Binding
  2. Reaction
33
Q

Binding Specificity

A

Enzymes may bind very specific substrates or broad substrates
(Either very specific with what it binds to or not very specific at all)

34
Q

Reaction Specificity

A

Depends on the specific functional groups (amino acids) present in active site

35
Q

Kcat (Catalytic Constant)

A

The number of substrates changed to product per second

36
Q

Mechanisms of Enzyme Catalysis (6)

A
  1. Approximation
  2. Covalent
  3. Acid/Base
  4. Electrostatic
  5. Desolvation
  6. Strain/distortion
37
Q

Approximation

A
  • Rate acceleration via proximity, how close they are
  • Enzyme-substrate are positioned close and in preferred geometry
38
Q

Covalent Catalysis

A

Enzymes covalently bind to substrates and can act as leaving group

39
Q

Two Kinds of Acid/Base Catalysis

A
  1. Specific
  2. General
40
Q

Specific Acid/Base Catalysis

A

Determined by [H3O+] or [OH-] (pH)

41
Q

General Acid/Base Catalysis

A

Determined by increase in [Buffer] at constant pH

42
Q

Electrostatic Catalysis and Desolvation

A
  • enzymes stabilize intermediates or destabilize ground states
  • desolvation (removal of water) can destabilize ground states promote electrostatic catalysis
43
Q

Strain or Distortion Catalysis

A
  • Strained molecules are more reactive
  • the more an enzyme distorts the substrate, the faster the rate of the reaction
44
Q

Cofactors

A

Non-protein molecules that are required for enzyme catalysis and are broken down into two categories

45
Q

Coenzyme

A

Small organic molecules that loosely bind or fit into an active site to assist in catalysis and are often derived from vitamins

46
Q

Reversible Inhibition

A

Inhibition of the enzyme is temporary, and the interactions are not covalent
(Competitive for the active site)

47
Q

Irreversible inhibition

A

Inhibition of the enzyme is permanent and enzyme cannon regain activity, usually involves covalent interactions

48
Q

Why does dosing matter?

A

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
Q

IC50 Value

A
  • 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
Q

Approaches to Designing Reversible Inhibitors(4)

A
  1. Simple Competitive Inhibition
  2. Alternative Substrate Inhibition
  3. Transition State Analogue Inhibition
  4. Slow Tight Binding Inhibition
51
Q

Simple Competitive Inhibition

A
  • bind quickly and reversibly
  • inhibitors tend to have similar structure to natural substrate or product of enzyme
  • usually start with structure of substrate
52
Q

Alternative Substrate Inhibition

A
  • 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
Q

Antimetabolites

A

Drugs that are chemically similar to necessary metabolites (purines, pyrimidines, folate) and interfere in biosynthesis of that metabolite

54
Q

Prodrugs

A

Start as an inert compound but get metabolized into an active form (pharmacokinetics)

55
Q

Transition State Analogue Inhibition

A
  • 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
Q

Slow Tight Binding Inhibition

A
  • reach equilibrium between enzyme and inhibitor slowly
    (Kon = small; Koff = small)
  • unknown causes
57
Q

Competitive Inhibition

A

Substrate and Inhibitor compete for the same active site - affect slope of the plot

58
Q

Uncompetitive Inibition

A

Inhibitor only binds the enzyme/substrate complex (only effective at high substrate concentrations) - affects only y-intercept of plot

59
Q

Noncompetitive Inhibition

A

Inhibitor can bind to both the enzyme and enzyme/substrate complex - affects both slope and y-intercept (AKA mixed inhibitor)

60
Q

Irreversible Inhibitors

A

Enzyme and inhibitor are bound covalently and permanently - no Koff

61
Q

Irreversible Inhibitors (types (2))

A
  1. Affinity Labeling Agents
  2. Mechanism-based enzyme inactivators
62
Q

Affinity Labeling Agents

A
  • contain reactive electrophile groups
  • tend to be less selective and more toxic
  • covalently bind to nucleophiles in the active site
63
Q

Mechanism-based enzyme inactivators

A
  • 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
Q

Difficulties of using DNA as Drug Targets

A
  • 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
Q

DNA Structure for Druggability

A

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
Q

Reversible Binders

A

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
Q

Alkylators

A

React covalently with DNA bases like irreversible inhibitors

68
Q

Strand Breakers

A

Generative reactive radicals that cleave polynucleotide strands (especially toxic)

69
Q

Minor Groove Binders

A
  • targeted by drugs and small molecules
  • specifically wants A-T rich regions
  • displaces water along the groove and widens the groove
70
Q

Intercalators

A
  • aromatic and flat
  • insert between DNA bases
  • does NOT interrupt hydrogen binding
  • causes DNA distortion
71
Q

Bisintercalators

A
  • bind two strands of DNA
  • greater affinity for DNA
72
Q

Alkylators

A
  • 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
Q

Difficulties of Lipids as Drug Targets

A
  • hydrophobic, not soluble if taken as a pill
  • minimal receptor activity
  • no charge, difficult targets
74
Q

2 Hypotheses for Polyene mechanism of action

A
  1. Ergosterol sponge
  2. Ergosterol binding and pore formation
75
Q

Penicillin

A

The miracle drug, targets material that only bacteria possess

76
Q

Two Hypotheses for DNA strand breaking

A
  • reduction of anthracycline core leads to hydroxyl radical
  • iron complexed anthracycline can undergo Fenton reaction to form hydroxyl radicals

Medicinal Chemistry (2 decks)

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