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cadd Flashcards

1
Q

general use of computers from hit generation to lead optimization

A

Computer-aided drug design (CADD)

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2
Q

Computer-aided drug design (CADD) is the general use of computers from ___________ to ________

A

hit generation; lead optimization

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3
Q

specific use of computers
when still filtering out massive amounts of chemicals

A

Virtual screening

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4
Q

T/F: CADD is omplementary to biological (in vitro/ in vivo) screening to reduce uncertainty in finding promising molecules

A

True

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5
Q

In drug discovery, the common goal at the molecular level is binding of the __________ and the _________

A

ligand; drug target

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6
Q

The main players in CADD should be the _______
and the __________

A

ligand; drug target

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7
Q

Ligand-based drug design (LBDD) is based entirely on the _______________

A

hit/lead compounds

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8
Q

Done in the absence of data for the drug target

A

Ligand-based drug design (LBDD)

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9
Q

T/F: LBDD does not requires similar compounds that work already
exist

A

False; requires

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10
Q

Where are drug molecules studied

A

Ligand-based drug design (LBDD)

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11
Q

You already know the information about the drug
molecules, receptor, and the drug target

A

Structure-based drug design (SBDD)

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12
Q

T/F: SBDD is done in the presence of the drug target

A

true

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13
Q

SBDD is based on _________________ between the
drug target and the hits/leads

A

measuring interactions

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14
Q

CADD OUTLINE

A

● Preparing the ligand
● Ligand-based Drug Design (LBDD)
● Receptor modelling
● Structure-based Drug Design (SBDD)

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15
Q

PREPARING THE LIGAND includes

A

DRAWING THE MOLECULE
ENERGY MINIMIZATION

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16
Q

Various software packages are available which can be used to construct molecules quickly to professional standard

A

DRAWING THE MOLECULE

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17
Q

T/F: you can place atoms freely but can end up with a weird result

A

true

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18
Q

T/F: you just need to enter a code and the program auto-draws it properly

A

True

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19
Q

pertains to a certain code so the program can provide the 3D structure

A

SMILES

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20
Q

Free-style drawing programs allow a person to make unrealistic molecular models

A

ENERGY MINIMIZATION

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21
Q

T/F: Unrealistic models can’t predict anything properly

A

True

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22
Q

Unrealistic = _____________

A

high energy

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23
Q

___________ makes non-ideal bonds, angles, and
other geometries more realistic

A

Minimization

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24
Q

Minimizaion is usually carried out by a __________ which corrects everything automatically

A

molecular mechanics
program

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25
Q

LBDD includes

A

SIMILARITY SEARCHES
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (2D QSAR)
PHARMACOPHORE MODELLING

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26
Q

Similarity property principle (SPP):

A

Similar compounds should have similar properties

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27
Q

Easiest way for a beginner to understand structure-activity relationships in medicinal chemistry

A

Similarity searches

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28
Q

T/F: Similarity is avoided by companies due to intellectual property rights and patents

A

True

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29
Q

phenomenon where a very slight change in two similar-structured compounds spell a night-and-day difference in their activity

A

Activity cliff

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30
Q

CBZ, Amitriptyline, Loratadine have the same parent compound: _____________ but they differ on the substituents

A

dihydro dibenzo annulene

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31
Q

CBZ or Carbamazepine is an ____________

A

anticonvulsant

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32
Q

Amitriptyline is an ___________

A

antidepressant

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33
Q

Loratadine is an ____________.

A

antihistamine

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34
Q

T/F: Similarity is quite subjective

A

True

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35
Q

T/F: Assumptions on similar compounds can be
made by the best medicinal chemists in the world and still be proven wrong when experiments prove unexpected activity cliffs

A

True

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36
Q

attempts to make similarity judgments more objective

A

Similarity coefficients

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37
Q

examples of similarity coefficient

A

Tanimoto (Tc), Tversky (Tv), and Dice coefficients (Dc)

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38
Q

most common similarity coefficient

A

Tanimoto

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39
Q

In _____________, the coefficient should be computed based on the similarity of the constituents present in the particular compound.

A

Tanimoto

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40
Q

T/F: coefficients can distinguish similarity relationships in a consistent manner

A

True

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41
Q

The higher the tanimoto coefficient = the _____________ the similarity

A

higher

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42
Q

An alternative to similarity coefficients

A

structure overlay

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43
Q

Root mean square distance (RMSD) measures how “___________” all the atoms are

A

different

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44
Q

lower RMSD = ________ similar and ________
reliable

A

more;more

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45
Q

In structure overlay it is important that molecules are already in ______________ (active/inactive) conformation since molecules are assumed to be rigid

A

active

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46
Q

Good with rigidity:

A

Less calculation time

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47
Q

Bad with rigidity:

A

Less realistic (molecules
constantly move!)

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48
Q

Attempts to convert physicochemical properties of a
potentially active molecule into plots or equations

A

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (2D QSAR

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49
Q

Physicochemical properties:

A

partition coefficient,
solubility, polarity, etc.

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50
Q

By quantifying physicochemical properties, it should
be possible to “________” if a compound is active or
not

A

estimate

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51
Q

T/F: QSAR is done in wet lab

A

False: QSAR is strictly computational/dry lab

52
Q

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (2D QSAR) is used to compare actual activity and phase predicted
activity of a test compound through _________

A

linear regression method

53
Q

F/T: QSAR is often done at the start of a project

A

True

54
Q

f a screening molecule does not fit a QSAR equation/plot, it implies that it is (active/not active)

A

not active

55
Q

direct biological activity is used for computation; harder to interpret

A

Free-Wilson Approach

56
Q

A ‘flow diagram’ which allows initial QSAR for a
small number of compounds

A

Topliss Scheme

57
Q

Used when compounds are too few for a reliable
Hansch equation

A

Topliss Scheme

58
Q

A plot where the y-axis is σ (EWG/EDG power) and the x-axis is π (hydrophobicity).

A

Craig Plot

59
Q

Useful in planning which should be used in a
QSAR study

A

Craig Plot

60
Q

allows the medicinal chemist to identify substituents which may be potential substitutions/ bioisosteres for synthesis

A

Knowledge of QSAR-derived constants

61
Q

QSAR properties

A

Hydrophobicity
Electronic Effects
Steric Factors

62
Q

Often measured by the partition coefficient (P) or more often, its logarithm (logP)

A

Hydrophobicity

63
Q

relationship of partition coefficient, nonpolarity, hydrophobicity, metabolism, activity

A

directly proportional

64
Q

measure of how hydrophobic a substituent is relative to hydrogen

A

Substituent hydrophobicity constant (π)

65
Q

A _____________ (postive/negative) value of π indicates that the substituent is more hydrophobic than hydrogen

A

positive

66
Q

T/F π values for aromatic substituents are different from those used for aliphatic substituents

A

True

67
Q

measure of the electron withdrawing or electron-donating ability of a substituent

A

Hammett substituent constant (σ)

68
Q

Electron withdrawing substituents/
groups (EWG

A

Cl, Br, halogens, ketone,
aldehyde, carboxylic acid, carbonyl

69
Q

(-) Electron-donating substituents/ groups (EDG):

A

Methyl (CH3), OH, NH3

70
Q

T/F; Electronic effects are Based on probability of hydrolysis

A

True

71
Q

A bulky substituent may act like a shield and hinder the ideal interaction between a drug and its binding site

A

Steric Factors

72
Q

a bulky substituent may help to orientate a drug properly for ____________ (maximum/minimum) binding and ___________ (increase/decrease) activity

A

maximum; increase

73
Q

portion/regions of a drug molecule that gives it its activity

A

Pharmacophore

74
Q

“Face” of the molecule that interacts with the
receptor

A

Pharmacophore

75
Q

pharmacophore
of most Cell Wall Synthesis Inhibitor (CWSI) antibiotics (Penicillin, Carbapenem, Cephalosporin)

A

β-lactam ring

76
Q

T/F: pharmacophore is a specific compound or functional group

A

False; it is not

77
Q

Pharmacophores are __________, polygon-like figures where points represent features that a hit compound must satisfy

A

abstract

78
Q

Pharmacophore is usually __________ based and is using almost similar compound

A

ligand

79
Q

When finding a new pharmacophore, it is required that the actives are already rigid in their ___________ (inactive/active) conformation

A

active

80
Q

If there are multiple active compounds, their conformations can be assessed to determine the ____________ (or “centers”) their substituents occupy

A

common spaces

81
Q

When those centers are identified across compounds, the program forms the final ligand-based pharmacophore model a.k.a. _____________-

A

pharmacophore hypothesis

82
Q

T/F: The centers must have defined IMFs

A

true

83
Q

T/F: Sometimes the model doesn’t connect those
points, but the points are enlarged to visible spheres
or arrows

A

True

84
Q

Receptor modelling include

A

XRC
Homology modelling

85
Q

Used for various materials in the crystallized state to determine the arrangement of atoms within a crystal

A

XRC

86
Q

XRC
is a __________ method – you need a real protein
sample and a real X-ray generator

A

biophysical

87
Q

Receptors models from XRC are often definitive and
best for ________

A

SBDD

88
Q

T/F: XRC can also be used to determine active conformations,
and consequently, pharmacophores

A

True

89
Q

The main problem of XRC is that many proteins are

A

hard to crystallize

90
Q

same name, different organisms

A

Homolog

91
Q

T/F: Human and bacterial hexokinase are homologs

A

True

92
Q

using X-ray structures from other organisms’ proteins to create your own protein

A

Homology modelling

93
Q

Homology modelling is done whenever there is no __________ yet of
the protein in the target organism

A

X-ray structure

94
Q

Homology remodelling requires

A

■ crystal structure of a homolog (template)
■ protein sequence from target organism
(copies the template structure)

95
Q

Steps in homology remodelling

A

1) identify primary model
2) Identify sequence identity thru sequence allignment
3) model refinement

96
Q

T/F: Homology remodelling suffers from multiple error sources

A

true

97
Q

STRUCTURE-BASED DRUG DESIGN includes

A

Molecular docking
Molecular dynamics simulation
Fragment based drug design
De Novo Drug Design

98
Q

T/F: Under SBDD, IMFs are not anymore assumptions but real interactions between drug and receptor

A

True

99
Q

convert energy values from the said IMFs into “scores” that correspond to how good a molecule can affect the target or not

A

SBDD programs

100
Q

Lesser energy = _________ (better/worse_ drawing of the structure

A

better

101
Q

T/F: Shape is still included in the SBDD.

A

False; Shape is no longer included in the SBDD.

102
Q

Involves “docking” or fitting the ligand to the target/receptor

A

Molecular docking

103
Q

T/F: Molecular docking does not need known actives

A

True

104
Q

The calculations required for docking and scoring have to be ________ in order to process the number of molecules

A

rapid

105
Q

most commonly done type of dockin

A

Style 1

106
Q

essentially what we call molecular
dynamics

A

Style 3

107
Q

identified through X-ray crystallography, homology modelling, and
NMR

A

Protein data bank (PDB)

108
Q

T/F: Good docking programs should have a good scoring system, rewarding higher scores for better potential ligands (and vice-versa)

A

True

109
Q

Main hurdles for docking:

A

-interference of water molecules
-protein flexibility
- flexible
ligands

110
Q

esigned to mimic the movement of atoms within a molecule or complex

A

Molecular dynamics

111
Q

T/F: MD simulations prove or disprove uncertainties that docking (by virtue of being stationary) can never answer

A

True

112
Q

Programs that perform MD use “__________” which are collections of mathematical formulas that try to make MD simulations as realistic as possible

A

force fields

113
Q

__________ pertain to the “algorithms developed by countless mathematicians and physicians” mentioned earlier

A

force fields

114
Q

T/F: MD Has to be realistic, so even temperature, pressure, ion concentration, etc. should be consistent and recorded

A

True

115
Q

T/F: In MD, The person running the simulation has controls over
literally everything

A

True

116
Q

Uses docking or dynamics on “fragments” of a ligand instead of complete molecules

A

FRAGMENT BASED DRUG DESIGN

117
Q

Fragment based drug design starts with the ___________, then more flexible
“fragments” are added layer per layer

A

rigid part (anchor)

118
Q

T/F: fragments may be tailor-fitted for different receptors

A

True

119
Q

Pilot test; virtual screening

A

DE NOVO DRUG DESIGN

120
Q

Ligand structure is _______; protein structure is
________

A

unknown; known

121
Q

De novo drug design disadvatage

A

There is a lack of related study which
makes it prone to certain errors.

122
Q

De novo drug design focuses on

A

proof of concept based on the new fresh
idea

123
Q

In Denovo drug design, the novelty of the structures obtained is limited to
the operator’s own ___________ and ________

A

imagination and originality

124
Q

the real strength in de novo drug design is that

A

can stimulate new ideas and identify novel lead
structures

125
Q

De novo is Very experimental and arbitrary

A

ddd (3 decks)

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