Lecture 7: QSAR and Drug Development Flashcards

1
Q

QSAR (Quantitative Structure-Activity Relationship)

A

-math models showing correlation between drug structure and actiivties
-derived by statistical regression
-information on receptor not necessary

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2
Q

Molecular Descriptors

A

-numerical parameters describing chem properties that can be directly determined from structure
-used as variables in QSAR models

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3
Q

Molecular descriptors examples

A

-drug as whole: LogP and D, molecular weight, pKa
-fragments: pi and sig values, size

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4
Q

Hansch Analysis

A

log (1/dose) = k+k’(logP)-k”(logP)^2 + other terms

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5
Q

Training

A

determines parameters (P1, P2, etc) of math models using a training set

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6
Q

Testing

A

checks validity of model using a test set

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7
Q

Training and Testing

A

-both sets contain drugs with known activity data
-can be used to predict activity of drug without known activity data

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8
Q

Mathematical Model example

A

Activity = P1 * pi value
+ P2 * sig val
+ P3 * molecular weight
+P4 * LogP
+C

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9
Q

Machine learning

A

-provide computer with extensive set of data and let it determine QSAR itself
-no math model needed
-bases of SAR is not apparent

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10
Q

Machine learning Mech

A

Structures –(molecule vectorization)–> inputs –(multiple hidden layers)—> hidden layers —–>outputs (probabiility affinity)

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11
Q

Drug Discovery and development

A

Research –> target -(lead discovery)-> lead -(lead optimization)-> drug candidate –> trials

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12
Q

Lead discovery

A

-natural products
-antimetabolites
-structure-based drug design
-high throughput screen
-in silico drug screen

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13
Q

Lead optimization

A

-structure based drug design
-QSAR
-isoteric replacement
-prodrug

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14
Q

Antimetabolites

A

-analogues of endogenous metabolites
-resemble essential metabolite and competes with metabolite in physiological reactions
-folic acid vs methotrexate

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15
Q

Structure-based drug design

A

-based on 3D structure of target protein
-rational design vs in silico screen

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16
Q

Zanamivir (relenza)

A

-flu neuraminidase inhibitor
-DANA was a transtition-state analogue
-improved binding by switching hydroxyl group with guanidino group
-approved inhaler for flu
-KI = 2 * 10 ^(-10)

17
Q

DANA

A

-transition state analogue
-KI = 1 * 10^(-6)

18
Q

Challenges of drug design

A

-potency
-solubility
-stability
-selectivity
-permeability

19
Q

Bioisosteres

A

-functional groups or atoms that:
-have similar steric and electronic properties
-produce similar effects on target

20
Q

Bioisosteric replacement

A

-improve pharmacokinetics
-improve selectivity
-reduce side effects
-simplify synthesis process
-avoid patent issues
-haloperidol?

21
Q

Examples of bioisosteres

A

-H and -F
-aromatic rings
-S or =O bond

22
Q

Prodrug

A

-inactive/carrier form of drug that is transformed in vivo to active drug form (usually via enzyme)

23
Q

Prodrug uses

A

-prolong or shorten duration
-help localize drug to specific target site
-take advantage of active transport
-solve formulation problem
-decrease side effects

24
Q

Heroin

A

-prodrug
-changes to morphine via esterases

25
Q

Remdesivir (veklury)

A

-prodrug
-antiviral
-treat COVID
-converted to nucleotide analog that interferes with viral RNA production

26
Q

You have crystallized your drug with its receptor. You see some room currently occupied by a water molecule, which makes a hydrogen bond with a positively-charged lysine group. You decide to add a group to the starred carbon to enhance the binding affinity of the drug. What group do you think will be best at that position?

A

Something that will make an OH

27
Q

Which of the following methods is not a suitable approach for lead discovery?

A

Isoteric Replacement