relating small molecule structure to small molecule performance
DESCRIPTION
Relating Small Molecule Structure to Small Molecule Performance. Establishing structure-activity relationship (SAR) for novel disaccharides exposed to preadipocyte cell states. Isaac Joseph. Why is finding SAR useful?. Drug development Effect enhancement through structure optimization. - PowerPoint PPT PresentationTRANSCRIPT
ESTABLISHING STRUCTURE-ACTIVITY RELATIONSHIP (SAR)
FOR NOVEL DISACCHARIDES EXPOSED TO PREADIPOCYTE CELL
STATES
Relating Small Molecule Structure to Small
Molecule Performance
Isaac Joseph
Why is finding SAR useful?
Drug developmentEffect enhancement through
structure optimization
How did we previously assess SAR?
Visual inspection of data and structures Introduces bias Time -consuming
Computational analysis – often used with isolated proteins Doesn’t account
for cellular context Usually deals
with only onebiological outcome
How do I assess SAR?
1. Describe structure and performance2. Alter structure description to match
performance3. Interpret results
How do we describe elements of small molecule structure?
regiochemistry
O O
O
OH
OH
O
O
OH
OHHO
O O
O
O
O
OH
OHHO
OH
OH
1
4
1
2
structural descriptors
How do we describe elements of small molecule structure?
stereochemistry
O O
O
OH
OH
O
O
OH
OHHO
O O
O
OH
OH
O
O
OH
OHHO
structural descriptors
How do we describe elements of small molecule structure?
appendages
O O
O
OH
OH
O
O
OH
OHHO
O O
O
OH
OH
O
O
OH
OHHN
HO
O
structural descriptors
How do we represent small molecule structure computationally?
50 descriptors
structure matrix structural descriptors
presence absence
What biological effects were measured?
5 preadipocyte cell statesWild-type brown preadipocyteIRS 1 -/- brown preadipocyteIRS 2-/-
brown preadipocyte3T3- L1 white preadipocyteTunicamycin modified white
preadipocyte2 measured effects
Lipid accumulationMitochondrial membrane potential
How do we represent biological effects computationally?
performance matrix
80 assays (2 columns each for +, - effects)effect no effect
How do I assess SAR?
1. Describe structure and performance2. Alter structure description to match
performance3. Interpret results
Step 1: Calculate similarities between small molecules in performance
performance matrix
64 small molecules64
sm
all m
olec
ules
pairwise performance similarity
64 s
mal
l mol
ecul
es
80 assayseffect no effect
dissimilar similar
Step 2: Calculate similarities between small molecules in structure using partial
description
64 small molecules
64 s
mal
l mol
ecul
es
pairwise structure similaritypick a subsetpick a subset
8 descriptors
64 s
mal
l mol
ecul
es
candidate structure matrix
structure matrix
64 s
mal
l mol
ecul
es
50 descriptors
dissimilar similar
presence absence
Step 3: Check similarity between performance and structure
64 small molecules
64 s
mal
l mol
ecul
es
pairwise performance similarity
64 small molecules
64 s
mal
l mol
ecul
es
pairwise structure similarity
dissimilar similar dissimilar similar
p-sugar (methyl)
r- sugar (methyl)
LL
p-sugar( mannose | ribose)
r-sugar (mannose |
rhamnose| ribose)
r-sugar (C1 S | C4R)
p-N-acetyl
pairwise performance similarity
64 small molecules
64 s
mal
l mol
ecul
es
64 small molecules
pairwise structure similarity
optimized pairwise structure similarity
64 s
mal
l mol
ecul
es
64 small molecules
64 s
mal
l mol
ecul
es
64 s
mal
l mol
ecul
es
Step 4: Change structural description until similarity between performance and
structure is maximum
all descriptorsall descriptors selected descriptorsselected descriptors
How do I assess SAR?
1. Describe structure and performance2. Alter structure description to match
performance3. Interpret results
How do we know it’s working?
p < 0.046 p < 0.046
performance matrix
columns permuted22 times
optimized structure
similarity matrix
What do the selected structures mean?
O O
O
OH
OH
O
O
OH
OHHO
O O
O
O
O
OH
OHHO
OH
OH
O O
O
OH
O
O
OH
OH
OH
OH
selected descriptors
8 small molecules
p-sugar (methyl)
r- sugar (methyl)
LL
p-sugar( mannose | ribose)
r-sugar (mannose |
rhamnose| ribose)
r-sugar (C1 S | C4R)
p-N-acetyl
performancesimilarity matrix
Acknowledgements
Paul A. Clemons (mentor)Joshua C. GilbertNicole E. Bodycombe
Analysis
Chemistry
Biology
Micha FridmanTetsuya Tanikawa
Daniel Kahne
Bridget K. Wagner
AdministrationShawna L. YoungBruce Birren