Comp in DD - Grayson Flashcards
Define ligand based drug design?
Design of a drug with no structural information on the biochemical target. Relies on knowledge of other molecules that bind.
What is QSAR?
Quantitative structure activity relationship - identifying and quantifying the physiochemical properties of a drug to see if any correlate with biological acitivity.
What is Es?
Taft’s Steric Factor
What is MIC?
Minimum inhibitory conc - minimum conc needed to prevent visible growth of bacteria.
How does Es work?
Compares acid hydrolysis of an ester to a standard ester. RATE CONSTANTS!
CASE STUDY - Norfloxacin - ligand based
Ligand Based Drug Design
QSAR forund 6 and 8 position on ring.
h best at 6, flourine at 8
CASE STUDY - Lorsartan - ligand based
hypertension
lead compared with angiotensin 2 in solution
para substituents increased similarity
led to sartans- biphenyl tetrazole
CASE STUDY - Zolmitriptan - ligand based
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
Define Pharmocaphore
steric and electronic features needed to ensure optimal supramolecular interactions with a biological target and trigger/inhibit a response
Define Structure based Drug Design
Design based on knowledge of the 3d structure of the biological target.
Case Study - Dorzolamide - structure based
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
Case Study - Zamaivir - structure based
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
Case Study - Amprenavir - structure based
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
Define virtual screening
computational method used to analyse databases of compounds to identify potential HIT compounds.
CASE STUDY - 4SD-101 - virtual screening
1000s to 55
qsar then used
activity better with -ve hydrophobic
worse with high Mr and volume
Define Supersaturation
A solution with more dissolved material than normally possible under standard conditions
Define Molecular Docking
prediction of binding mode of a compound with active site. Also predicts strength of binding.
Define NON-covalent interactions
interactions not involving the sharing of electrons.
Define key points of protein crystalisation
supersaturation needed noncovalent packing interactions lots of solvent in crystal loose packing means poor diffraction soaking - small molecules through solvent channels HARD TO DO!
How do you solve the phase problem?
Molecular replacement - similar structures
Isomorphous replacement - heavy atom, minimal structural change, difference used to estimate phase
What causes error in diffraction patterns?
non static atoms
different conformation/position
Define molecular mechanics
Using classical mechanics to model molecular systems. potential energy calc as a function of nuclear coordinates.
Molecular modelling MM
atoms every atom interacts with every other atom 10^4 to 10^6 atoms simple mathematical models - hookes law distortion from ideal value
Molecular modelling QM
Nuclei and Electrons
100-200 atoms
ACCURATE!
