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Drug discovery > Appunti > Flashcards

Appunti Flashcards

1
Q

Definition of intrinsic solubility

A

Solubility of the compound in its free acid or free basic form (pH indipendent)

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2
Q

Which are the 3 steps of solubility?

A

1- Dissociation of the molecule from the crystal: depends from the strength of the interaction between the particle of the solid
∆G is positive: the process require energy.
2- Formation of a cavity in the solvent: it depends on the strength of the interaction of the molecule of the solvent. ∆G is positive: the process require energy.
3- Insertion of the molecules in the solvent cavity.
∆G is negative: the process produce energy.

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3
Q

Definition of solution

A

Liquid in which the solute is completely solubilized (transparent)

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4
Q

What is the constant of polarity?

A

It’s a characteristic of each solvent. water has 80

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5
Q

Which kind of solvent can we recognize according to the polarity? (with examples)

A

Polar solvent: partial charge on the atom (water).
Apolar solvent: no charge (hexan, benzene, toluene, chlorophormio)
Apoprotic solvent: no proton can dissociate (aceton, do-metyl- formaldeide)
Protic solvent: the H are bound to a polar atom, one or more proton can dissociate (methanol, ethanol)

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6
Q

Describe the coloumb equation.
How is the constant of a polar solvent?

A

the dielectric constant is inversely proportional to the interaction of charges with each other.
Polar solvents shows high dielectric constant

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7
Q

What’s DMSO?

A

It’s a co-solvent used to solubilize compounds that cannot be solubilized in water. It does not affect cells of at [1-5%]

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8
Q

Which problems does DMSO use cause?

A
  • it might modify the physical and chemical properties of the compound
  • it’s toxic for patients
  • the compound shows a different behaviour than in vivo
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9
Q

How can we measure pH?

A

Indicators paper (semi quantitative) or pHmeters (quantitative)

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10
Q

How can we calculate the pH of a solution?

A

-log[H+]

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11
Q

Write the equation of ionization of an acid

A

HA <-Ka->A- + H+

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12
Q

Definition of pKa

A

The pH at which a substance is 50% ionized so it’s the measure of how easily a proton is removed from an ionized base/acid

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13
Q

When pH = pKa?

A

When the concentration of ionized and non-ionized specials are equal

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14
Q

What’s the use of an ionization plot?

A

It’s used to verify which is the dominant specie of a compound at a given pH

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15
Q

How can we build a ionization plot?

A

1- draw the plot: x = pH, Y = % of species
2- indicate the 2 species that we’re considering
3- indicate the pKa (pH when % is 50)
4- acid pH -> AH =100%
basic pH -> AH=0%
5- acid pH -> A- = 0%
basic pH -> A- = 100%

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16
Q

Write the general equation of equilibrium for acid and base

A

Base:
BH+ <-> H+ + B

Acid:
AH <-> H+ + A-

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17
Q

Definition of zwitterion with example

A

Specie that have both an acidic and a basic functions.
An example is alanine

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18
Q

Draw the ionization plot of alanine

A

…

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19
Q

Which methods can we use to measure pKa?

A

Potentiometric method
Spectrometric method

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20
Q

Describe how the potentiometric method work

A

1- we have to do the blank titration by adding chlorhydric acid to water (reaching acid pH) and then KOH (base). The instrument measure pH variations and give a graph
2- then we do the same using water with the sample solubilized
3- we compare the two graph with on the Y the avarage number of each atom bound to the molecule and on the X the pH. pKa = pH when there is half of the bound

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21
Q

Describe the spectrometric method

A

You need to start to a molecule with a chromophore close to the ionization site (es: Warfarin).
Then you measure the UV spectra for:
- 100% neutral specie
- 100% ionized species
- 2 solution with both
and measure their absorbance at the best wavelenght.
Using the Handerson ahasselbalch equation you can obtain the pH and the pKa.

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22
Q

How can I calculate the pKa of an aminoacid?

A

there are databases (chemspider, iBonD, PKAD) with the frequency of pKa for each amino acid

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23
Q

Definition of buffer

A

a solution that can mantain a nearly constant pH if diluted or if small amount of strong acid or bases are added

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24
Q

Definition of buffer capacity

A

the maximum amount of either strong acid or strong base that can be added before a significant change in the pH will occur

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25
Q

what happens if I add a strong base to a buffer?

A

considering a solution with a weak acid HA and its conjugate base A-, the weak acid will give up its H+ to transform the strong base OH- in water
HA + OH- = A- + H2O
The strong base OH- is consumed by the reaction so the pH change only slightly

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26
Q

What happens if a strong acid is added to a buffer?

A

considering a solution with a weak acid HA and its conjugate base A-, the weak base will react with the H+ from the strong acid forming a weak acid
H+ + A- = HA
The H+ gets absorbed by the A- instead of water so there’s no formation of H3O+ so the pH change only slightly

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27
Q

List some common buffers

A

Acetic acid
phosphoric acid
carbonic acid
ammonia

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28
Q

How can we obtain a buffer?

A

We can buy it or there are buffer calculators that provide the recipe for a buffer at a specific pH

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29
Q

Definition of spectroscopy

A

Study of the interaction between matter and electromagnetic radiation that can result in either absorption or emission

30
Q

Definition of absorbance

A

logarithm of the ratio of incident to transmitted radiant power
A=log I0/I

31
Q

Definition of chromophore

A

the atom or any isolated covalently bound group of atoms responsible for the absorption of light reaction. they always have at least one multiple bond

32
Q

Examples of chromophores

A

Aromatic rings
Esters
Carbonyls (=O)
Carboxyl group (C =O, -OH)

33
Q

Definition of auxochromes

A

Atoms or group of atoms which do not absorb radiation by themselves but when they’re present close to a chromophore, they enhance or modify its absorbing properties.
They all have at leas one non-bonding electron

34
Q

Examples of group that works as auxochromes

A

NH2 (free duplet of electrons above the N)
NHR
OH
SH

35
Q

Examples of group that works as auxochromes

A

NH2 (free duplet of electrons above the N)
NHR
OH
SH

36
Q

Draw the UV-vis spectrum of toluene

A
37
Q

How can we compare two spectra?

A

We have to compare the peak and the position:
- more intense peak = hyperchromic effect
- less intense peak = hypochromic effect
- spectra moved to the right = batochromic effect
- spectra moved to the left= ipsochromic effect

38
Q

What do we need to record a spectrum?

A

A cuvette to put the solution on (glass 200-800 or quartz)
A blank
A immunospectrophotometer
If we have a lot of samples we can use a microplate and a microplate reader

39
Q

Which factors impact on the UV spectrum ? list

A

Solvent cut-off
Buffer absorption
Solvent polarity
pH

40
Q

Definition of solvent cut-off and why is it important?

A

Wavelenght before which the solvent itself absorbs the radiations. we have to choose a solvent with a cut.off value that do not interfere with the wavelenght that we’re measuring.
Example: water cut-off is 180 so it doesn’t interfere with UV-Vis

41
Q

How can solvent polarity impact on UV spectra? with example

A

the polarity defined by the dielectric constant cause different UV spectra.
An example is acetone spectrum that shift using a non-polar solvent and a polar one (draw it)

42
Q

What kind of compound are influenced by the pH when measuring their UV-Vis spectrum?

A

Only ionizable compound have different spectrum at different pH expeciall according to the proximity of the ionizable group and the chromophore (if they’re far there isn’t a relevant variation).
The presence on a ionizable auxochrome have also a consequence:
- deprotonation of acid => bathochromic shift
- Protonation of base => ipsochromic shift

43
Q

What is and why is the beer-lambert law important

A

it define the linear relationship between absorbance and concentration:
A= e x c x L

44
Q

Definition of calibration curve

A

method for determining the concentration of a substance in an unknown sample by comparing the unknown to a set of standard sample of known concentration

45
Q

Which are the step necessary to draw a calibration curve?

A

1 prepare a series of solutions of the sample at different known concentration
2 measure the absorbances of the various solution
3 build a plot with the value
4 calculate the linear regression of the plot (Y=aX+b)

46
Q

Definition of R2

A

it’s a statistical parameter which represent the quality of the fitting procedure (0 to 1).

47
Q

What appens if the R2 is too low?

A

We can check for the presence of an outilier and eliminate it

48
Q

Which are the main structural features of fluorescent molecules?

A

they’re:
- UV active
- with aromatic rings fused together
- with structural rigidity due to multiple bonds and aromaticity

49
Q

Definition of quantum yield

A

it is the efficacy of the fluorescence process
= numbers of proton emitted / number of proton absorbed

50
Q

Characteristic and consequence of tagging a molecule

A

Tagging a molecule means modify its chemical structure and thus its properties and functions.
Tags are ionixed small molecules that may have biological activity

51
Q

What’s the quenching effect?

A

it is a modification in the environment that cause a decrease in fluorescence

52
Q

How can you synthetize peptides?

A
  • solution phase synthesis: you have 2 aminoacids in solution and you create a bond between them
  • solid phase synthesis: automatized, an aminoacid is immobilized on resin, the second is added and they bond

You always have to use protecting groups to avoid the formation of undesired bonds

53
Q

Describe an alpha helix

A

The polypeptide chain starts to twist to form a rod-like structure with a backbone and the R group on the outside. The rotation can be in clockwise direction (right hand helix) or in counterclockwise direction (left hand helix). The latter is much less stable because its energy level is higher.
There are single bonds, which instead allow rotation, and hydrogen bonds, between the NH of one amino acid and the CO of another four units ahead.

54
Q

describe a beta turn

A

The compactness of the polypeptide is granted by many sharp turns called beta turns or reverse turn, stabilized by H bonds. In these cases, the bond is between the CO of one amino acid and the NH group of the N+3 amino acid.
These turns are usually found on the surface of the polypeptide.
They’re the one that interact with the polar solvents found ouside the protein as well as the macromolecules that interact with the protein in general.

55
Q

describe an anti-parallel bet sheet

A

The groups line up one another perfectly: hydrogen donating group – hydrogen accepting group. This means that the NH and the CO group of an amino acid on one strand interact with the CO and NH groups of the opposing amino acid on the other strand.

56
Q

Decribe a parallel beta sheet

A

The two strands run in the same direction and an amino acid on one strand connect with two amino acids on the opposing strand via hydrogen bond.

57
Q

Which factors play a role in the formation of the tertiary structure ?

A

hydrophobic effect
hydrophobic interactions
van der walls interactions
disulfide briges
hydrogen bounds
ionic interaction

58
Q

How can we observe the structure of a protein?

A

We can perform an X-ray crystallography to obtain an electron density map

59
Q

definition of resolution

A

is the distance related to the smaller observable feature, the smaller the resolution, the better the structure

60
Q

How does TEM microscopy works?
How do you have to prepare the sample?

A

The electron beam is transmitted through a thin sample on a screen or camera detector that will show the protein.
You have to prepare the sample in condition of vacuum, transparency and lack of contrast where the biological samples are destroyed.
The main problem was how to get the protein in a form that can be analysed by an electric beam: you have to form a vitrified water that will immediately freeze your sample. Under these conditions, it could survive and be used to be analysed with an electron beam.

61
Q

What’s a FASTA file?

A

It is a text-based format for representing either nucleotide sequences or amino acid sequences in which nucleotide/amino acid are represented using single letter codes

62
Q

Definition of RMSD

A

measure of the average distance between the atoms of superimposed proteins

63
Q

List the steps necessary for homology modelling

A

Template recognition
Alignment correction
Backbone generation
Loop modelling
Side chain modelling
Model optimization
Model validation

64
Q

Which program can you use to perform homology modelling

A

Swiss model
alpha fold
Modeller

65
Q

How does alpha fold work?

A

It’s a protein structure database (AI system) that provides open access to 3D protein structures predictions.
So instead of homology model, it’s based on artificial intelligence. Anyway, it always starts from the experimental structure present in the PDB.
This software also calculates a predicted aligned error (PAE) plot: The colours indicate Alpha fold’s expected position error at residue x when the predicted and true structures are aligned on residue y. It allows you to understand the confidence that you should have in the protein.
The outputs of Alpha Fold are:
- The 3D structure of the protein
- The regions of high confidence
- The regions of low confidence

66
Q

What’s virtual screening?

A

It’s an ensable of computational tecniques used to search in libraries of small molecules for those structures that are more likely to bind a given drug target.
It can be ligand based or structure based

67
Q

What is the structure-based virtual screening?

A

It’s a procedure that allows to obtain the best fit between small and large molecules and so understand which of the small molecules have the highest skill to bind large ones.
The algorithm takes one or two molecules at a time and generate a number of poses, then it verify the capacity of every conformation determining the best pose for each ligand.
At the end it rank all the ligands according to specific criteria (scoring function):

68
Q

Which are the criteria of the ranking for structure-based virtual screening?

A

o Knowledge based: look how the crystallized ligand is bound to the pocket in PDB, and use this information to see which conformation of our compound is closer to the one reported in the PDB
o Energy based: a force field is used to calculate the energy of interaction between our conformer and the protein or the ligand and the receptor
o Empirical functions: the software optimizes, on the basis of available dataset, a function able to reproduce the experimental free energy of binding

69
Q

Which are the limitations of docking?

A

Docking has some limits:
- The entropic effect is not taken into consideration
- It treat the molecules as rigid bodies when in reality they can be flexible

70
Q

What’s the use of molecular dynamics?

A

It’s a strategy that allows to follow the movements of a protein in time.
It consists in solving the classical motion equations for atoms and molecules to describe their trajectory. These equations are solved by algorithms and in this way it is possible to describe how a protein is moving, which is strongly related to its physiological action.

71
Q

What’s a problem of molecular dynamics?

A

A problem of Molecular Dynamics is the timescale: the larger the protein, the higher the number of the equations to be solved, the longer the time.
Structural changes in vivo in proteins can take nanoseconds, microseconds, milliseconds, or longer.

Drug discovery (4 decks)

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