Comp in DD - Grayson

Question 1

Define ligand based drug design?

Answer 1

Design of a drug with no structural information on the biochemical target. Relies on knowledge of other molecules that bind.

Question 2

What is QSAR?

Answer 2

Quantitative structure activity relationship - identifying and quantifying the physiochemical properties of a drug to see if any correlate with biological acitivity.

Question 3

What is Es?

Answer 3

Taft’s Steric Factor

Question 4

What is MIC?

Answer 4

Minimum inhibitory conc - minimum conc needed to prevent visible growth of bacteria.

Question 5

How does Es work?

Answer 5

Compares acid hydrolysis of an ester to a standard ester. RATE CONSTANTS!

Question 6

CASE STUDY - Norfloxacin - ligand based

Answer 6

Ligand Based Drug Design
QSAR forund 6 and 8 position on ring.
h best at 6, flourine at 8

Question 7

CASE STUDY - Lorsartan - ligand based

Answer 7

hypertension
lead compared with angiotensin 2 in solution
para substituents increased similarity
led to sartans- biphenyl tetrazole

Question 8

CASE STUDY - Zolmitriptan - ligand based

Answer 8

migrane
5-HT 1b/1d agonist
pharmacophore from overlaying compounds
charged group
h bond acceptor
aromatic ring
volume which if occupied selects for 1d over 2a

Question 9

Define Pharmocaphore

Answer 9

steric and electronic features needed to ensure optimal supramolecular interactions with a biological target and trigger/inhibit a response

Question 10

Define Structure based Drug Design

Answer 10

Design based on knowledge of the 3d structure of the biological target.

Question 11

Case Study - Dorzolamide - structure based

Answer 11

interocular pressure, carbonic anhydrase 2 inhib
tested s and r enantiomers in active site
s better despite axial isobutly
work to favour it being there
added me group
chain shortened to reduce lipophilicity from me added

Question 12

Case Study - Zamaivir - structure based

Answer 12

Flu neuraminidase inhib
xray structure of natural inhib bound to enzyme
analysed for favourable interactions
replace OH with +ve substituent interacts -ve glutamate
lacked oral avaliability –> tamiflu

Question 13

Case Study - Amprenavir - structure based

Answer 13

HIV, HIV1 protease inhib
amide NH forms weakest H bond
dialkylsulfamide interacts with close h20
acts as scaffold for p1' and p2'
experimentally similar results

Question 14

Define virtual screening

Answer 14

computational method used to analyse databases of compounds to identify potential HIT compounds.

Question 15

CASE STUDY - 4SD-101 - virtual screening

Answer 15

1000s to 55
qsar then used
activity better with -ve hydrophobic
worse with high Mr and volume

Question 16

Define Supersaturation

Answer 16

A solution with more dissolved material than normally possible under standard conditions

Question 17

Define Molecular Docking

Answer 17

prediction of binding mode of a compound with active site. Also predicts strength of binding.

Question 18

Define NON-covalent interactions

Answer 18

interactions not involving the sharing of electrons.

Question 19

Define key points of protein crystalisation

Answer 19

supersaturation needed
noncovalent packing interactions
lots of solvent in crystal 
loose packing means poor diffraction
soaking - small molecules through solvent channels
HARD TO DO!

Question 20

How do you solve the phase problem?

Answer 20

Molecular replacement - similar structures

Isomorphous replacement - heavy atom, minimal structural change, difference used to estimate phase

Question 21

What causes error in diffraction patterns?

Answer 21

non static atoms

different conformation/position

Question 22

Define molecular mechanics

Answer 22

Using classical mechanics to model molecular systems. potential energy calc as a function of nuclear coordinates.

Question 23

Molecular modelling MM

Answer 23

atoms
every atom interacts with every other atom
10^4 to 10^6 atoms
simple mathematical models - hookes law
distortion from ideal value

Question 24

Molecular modelling QM

Answer 24

Nuclei and Electrons
100-200 atoms
ACCURATE!

Question 25

How does MM treat H bonds

Answer 25

partial charge

elecstatic with appropriate energy

Question 26

Define force fields

Answer 26

collection of equations and parameters used to calculate potential energy in MM.

Question 27

Define Molecular Dynamics

Answer 27

technique monitoring the time evolution of atoms
simulates natural motion of molecules by giving them energy to move, collide and overcome activation barriers between minima.

Question 28

CASE STUDY - Zamanivir (MM in design)

Answer 28

3d lattice on a grid
small probe moleulces
select favourable interactions
determin relative spacial orientations

Question 29

Define Database screening

Answer 29

docking chemicals from a database into the active site to find best fit.

Question 30

Define De novo

Answer 30

novel compounds docked for best fit

Question 31

Define scoring function

Answer 31

used in docking

mathematical function used to approximately find the binding affinity between a molecule and active site after docking.

Question 32

What do empirical scoring functions use to assess delta G?

Answer 32

VDW
Hydrophobic
H-bond
Deformation

Question 33

Define IC50

Answer 33

half maximal inhibitory concentration

Question 34

What is Free energy Perturbation

Answer 34

minimal step changed
perturbs one molecule into another
looking for equilib constants
k sol and k receptor used to find kb

Question 35

Define TS analogue

Answer 35

enzyme inhibitors which have been designed to mimic the TS of an enzyme catalysed reaction.

Question 36

CASE STUDY - TS analogue

Answer 36

angiotensin to AT1 to AT2
high energy tetrahedral intermediate
assumes TS more similar to the intermediate than reactants
targets lowest activation barrier. 
removed LG here!

Question 37

define kinetic isotope effect

Answer 37

change in rate of reaction when one atom is changed for one of its isotopes.