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

ekinssean@yahoo.com