Q&A
Pharmacophores for Drug Discovery
Sean Ekins
CYP2B6 J Pharmacol Exp Ther, 288:21-29, 1999
Q
What is a pharmacophore?
A
I think of it as the key features responsible
for an activity (e.g. substrates, inhibitors)
CYP2B6 J Pharmacol Exp Ther, 288:21-29, 1999
Q
Why did you start using pharmacophores?
A
I wanted to understand CYP2B6
substrates in 1996
CYP3A4 inhibitors J Pharmacol Exp Ther, 290:429-438, 1999
Q
What did you do differently?
A
I used the pharmacophores to predict
new molecules
CYP3A4 inhibitors J Pharmacol Exp Ther, 290:429-438, 1999
Q
What was it about them that made
them useful?
A
They were intuitive, simple, minimilist
and very visual
CYP3A4 inhibitors J Pharmacol Exp Ther, 290:429-438, 1999
Q
Why did you start on enzymes?
A
The lab I worked in had most
data on P450’s
CYP3A4 substrates J Pharmacol Exp Ther, 291: 424-433, 1999
Q
You seemed to focus on diverse
molecules, any reason?
A
We were looking at drug candidates
and drugs and some of the enzymes
were pretty promiscuous
CYP3A4 autoactivators J Pharmacol Exp Ther, 291: 424-433, 1999
Q
Why did you use this software?
A
It was available when I was a postdoc
and it was easy to use
CYP2C9 inhibitors Drug Metab Dispos 28: 994-1002, 2000
Q
Why use them beyond P450?
A
I wanted to stretch and see what
was possible, work on more complex
endpoints
In vitro Intrinsic clearance J Pharmacol Exp Ther, 295: 463-473, 2000
Q
Why so many pharmacophores
in each case?
A
We had our lab data and data from the
literature collated for the first time
Transporters and enzymes J Pharm Tox Methods, 44; 251-272, 2000
Q
Why are so many of the images
low resolution?
A
We were taking photos of the SGI
screen in many cases
Caco-2 permeability J Chem Inf Comput Sci, 41: 1578-1586, 2001
Q
What do you wished you had done
differently?
A
A review on pharmacophores from 2001
has no pictures – a missed opportunity
P450’s Drug Metab Dispos, 29: 936-944, 2001
Q
What was the turning point for you?
A
Probably the end of the postdoc (1998) -
modeling ADME/Tox would be the future
PXR Drug Metab Dispos, 30: 96-99, 2002
Q
Any one “stand out” moment or model?
A
No, two = hERG and PXR
hERG J Pharmacol Exp Thera, 301: 427-434 2002
Q
Do you see any repetition?
A
I see some similar pharmacophores
with different probe substrates
P-gp inhibition Mol Pharmacol, 61: 964-973, 2002
Q
Then what do you do when you see
repetition?
A
I try to look at overlap or ask why?
P-gp inhibition and substrates Mol Pharmacol, 61: 974-981, 2002
Q
Do all the pharmacophores receive interest?
A
No, CYP2D6 went under the radar for a long time
CYP2D6 inhbition Quant Struct Act Relat 21: 357- 368, 2002
Q
How has changing companies affected
what you do?
A
I manage to find some collaboration
that needs a simple model at the start
CAR Pharm Res 19: 1788-1800, 2002
Q
Any unexpected surprises?
A
Pharmacophores opened collaborations
that still continue
hOCT1 Mol Pharmacol 63: 489-498, 2003
Q
Any other surprises?
A
The same set of compounds for closely
related enzymes could reveal structural
insights
CYP 3A4, 3A5, 3A7 Trends Pharmacol Sci 24: 161-166, 2003
Q
Have you learnt anything from others
published data?
A
Yes, that they may have missed something
and I get to see it for the first time
hERG Drug Disc Today. 9: 276-285, 2004
Q
Any important implications?
A
Using phamacophores and other models
can reduce/ prevent need for animals
rbOCT2 and hOCT2 Drug Disc Today. 9: 276-285, 2004
Q
How have pharmacophores influenced your
work?
A
I worked a lot more on transporters and have
gone outside of ADME/Tox
hPepT1 Pharm Res, 22: 512-517, 2005
Q
What would surprise people about this work?
A
Most of it was performed without
NIH funding
OATPs J Pharmacol Exp Ther 314:533-541 2005
Q
How have companies responded to models?
A
Some papers took a long time to see daylight
hERG Pharm Res, 23: 1133-1143, 2006
Q
Why?
A
Projects died, people moved on, patents
that sort of thing lead to huge delays
CYP51 Drug Metab Dispos, 35: 493-500, 2007
Q
Did the models speed up science?
A
Yes we could cherry pick fewer compounds
P-gp Drug Metab Dispos, 34: 1976-1984, 2006
Q
Has focus on one technique affected you?
A
I have been able to publish using other tools
too and they may not always work best
CYP3A4 MIC Drug Metab Dispos, 35: 1466-1475, 2007
Q
How do you take something from the
past in new directions?
A
I keep looking for more collaborators
and more data
PXR agonists and antagonists Mol Pharmacol, 72: 592-603, 2007
Q
Are there projects that surprised you?
A
Yes working on compounds with
anticancer activity provided a new outlet
P-gp substrates and anticancer compounds J Med Chem, 51: 1242–1251, 2008
Q
What have been the most fun to work on?
A
Probably the evolution of nuclear receptors,
as I always wanted to do something
more fundamental
Human and ciona LXR J Steroid Biochem Mol Biol, 110:83-94, 2008
Q
When were you most prolific
using pharmacophores?
A
It comes in waves, 2001-2, 2007-2008
because of more data available to work on
or collaborations ongoing
PXR BMC Evolutionary Biology, 8:103, 2008
Q
What directions are left for modeling?
A
There will always be a place to gain
biological insights – I do not see
that going away
PEPT1 and PEPT2 Am J Resp Cell Mol Biol, 39: 536-542, 2008
Q
How has using multiple models been useful?
A
Gives more coverage of chemical space,
some models may fail
and others become useful
PXR Drug Metab Dispos, 36:1689-97, 2008
Q
Do you think the models might lead
to new drugs?
A
Most of the work is early stage,
but the PXR antagonists represent a
possible target of interest
PXR antagonists Mol Pharmacol, 74: 662-672, 2008
Q
Do you see cycling between targets
/ endpoints used for models?
A
I sort of alternate between PXR, transporters
and then miscellaneous uses
Immunoassay Trends Pharmacol Sci, 30:138-47, 2009
Q
How have they helped educate others?
A
They have suggested the features
they need to look for or avoid in
new molecules
OCTN2 Pharm Res, 26:1890-1900, 2009
Q
What was the biggest breakthrough
in the technology?
A
The shift to being able to use the software
on a laptop vs an SGI, speeded up modeling
and convenience
ASBT Mol Pharm, 6: 1591-1603, 2009
Q
As you move into new projects
pharmacophores go with you?
A
I try to find some use, not always possible
though
TB active compounds Mol BioSyst, 6: 840-851, 2010
Q
How do you approach revisiting models?
A
Use new data to test them, expand and
Improve them
OCTN2 Mol Pharm, 7: 2120-2131, 2010
Q
Has your use of pharmacophores for
understanding evolution taken off?
A
We have used the approach exclusively
for nuclear hormone receptors
Pufferfish nuclear hormone receptors BMC Biochem 12: 5, 2011
Q
What new uses have you envisioned?
A
Flipping the idea around to think of the
models to be of use for drug repurposing
OCTN2 Drug Disc Today, 16: 298-310, 2011
Q
Are there environmental consequences
of some models?
A
Models may help understand
how receptors evolved in response
to natural toxins in environment
Ciona VDR/PXR Toxicon, 59:365-72, 2012
Q
How have you expanded the use?
A
Thinking of individual essential molecules
as providing insight into a target enzyme
TB in vivo essential metabolites Pharm Res, 29: 2115-2127, 2012
Q
Where do you see potential growth areas?
A
Transporter substrates..
OCTN2 substrates Mol Pharmaceutics, 9:905-913, 2012
Q
Why are transporters of interest?
A
Modeling has lagged behind that of P450s,
importance of increased screening in
pharma to understand drug interactions
MATE J Pharmacol Exp Ther, 341: 743-755, 2012
Q
What is needed to facilitate this ?
A
More modelers working with groups
developing the data, methods to share
and test models collaboratively
NTCP Mol Pharmaceutics, 10:1008-19, 2013
Q
What do you see holding you back or limits?
A
Time, in vitro testing of models
Antimalarials Bioorg Med Chem Lett, 23: 1022, 2013
Q
Any new areas where shape is important?
A
Immunoassay cross reactivity – impacts
drugs of abuse and therapeutic drug
monitoring assay effectiveness
Methamphetamine and MDMA Clin Toxicol, 51(2):83-91, 2013
Q
Any other considerations people need to
be aware of?
A
How you dispense liquids may impact
your data which will influence your model
EphB4 pharmacophores PLOSONE, 8: e62325, 2013
Q
Any final words?
A
One pharmacophore is never enough
Credits
Collaborators on papers cited herein
Accelrys
With inspiration from
Charles Eames Design Q&A film
Contact
Collaborations in Chemistry
www.collabchem.com
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