This document is a Q&A with Sean Ekins about his work developing pharmacophores for drug discovery. Some key points: - He started using pharmacophores in 1996 to understand CYP2B6 substrates, and found them intuitive and useful for predicting new molecules. - Pharmacophores allowed him to work on more complex endpoints beyond just P450 enzymes, including transporters. - While some of his early work lacked high resolution images, the models still provided insights and suggested features to look for or avoid in new molecules. - Over time he expanded his use of pharmacophores to understand target evolution, drug repurposing, environmental impacts, and more. Transporters are an area

1. Q&A
Pharmacophores for Drug Discovery
Sean Ekins

2. CYP2B6
J Pharmacol Exp Ther, 288:21-29, 1999

3. Q
What is a pharmacophore?
A
I think of it as the key features responsible
for an activity (e.g. substrates, inhibitors)

4. CYP2B6
J Pharmacol Exp Ther, 288:21-29, 1999

5. Q
Why did you start using pharmacophores?
A
I wanted to understand CYP2B6
substrates in 1996

6. CYP3A4 inhibitors
J Pharmacol Exp Ther, 290:429-438, 1999

7. Q
What did you do differently?
A
I used the pharmacophores to predict
new molecules

8. CYP3A4 inhibitors
J Pharmacol Exp Ther, 290:429-438, 1999

9. Q
What was it about them that made
them useful?
A
They were intuitive, simple, minimilist
and very visual

10. CYP3A4 inhibitors
J Pharmacol Exp Ther, 290:429-438, 1999

11. Q
Why did you start on enzymes?
A
The lab I worked in had most
data on P450’s

12. CYP3A4 substrates
J Pharmacol Exp Ther, 291: 424-433, 1999

13. 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

14. CYP3A4 autoactivators
J Pharmacol Exp Ther, 291: 424-433, 1999

15. Q
Why did you use this software?
A
It was available when I was a postdoc
and it was easy to use

16. CYP2C9 inhibitors
Drug Metab Dispos 28: 994-1002, 2000

17. Q
Why use them beyond P450?
A
I wanted to stretch and see what
was possible, work on more complex
endpoints

18. In vitro Intrinsic clearance
J Pharmacol Exp Ther, 295: 463-473, 2000

19. Q
Why so many pharmacophores
in each case?
A
We had our lab data and data from the
literature collated for the first time

20. Transporters and enzymes
J Pharm Tox Methods, 44; 251-272, 2000

21. Q
Why are so many of the images
low resolution?
A
We were taking photos of the SGI
screen in many cases

22. Caco-2 permeability
J Chem Inf Comput Sci, 41: 1578-1586, 2001

23. Q
What do you wished you had done
differently?
A
A review on pharmacophores from 2001
has no pictures – a missed opportunity

24. P450’s
Drug Metab Dispos, 29: 936-944, 2001

25. Q
What was the turning point for you?
A
Probably the end of the postdoc (1998) -
modeling ADME/Tox would be the future

26. PXR
Drug Metab Dispos, 30: 96-99, 2002

27. Q
Any one “stand out” moment or model?
A
No, two = hERG and PXR

28. hERG
J Pharmacol Exp Thera, 301: 427-434 2002

29. Q
Do you see any repetition?
A
I see some similar pharmacophores
with different probe substrates

30. P-gp inhibition
Mol Pharmacol, 61: 964-973, 2002

31. Q
Then what do you do when you see
repetition?
A
I try to look at overlap or ask why?

32. P-gp inhibition and substrates
Mol Pharmacol, 61: 974-981, 2002

33. Q
Do all the pharmacophores receive interest?
A
No, CYP2D6 went under the radar for a
long time

34. CYP2D6 inhbition
Quant Struct Act Relat 21: 357- 368, 2002

35. Q
How has changing companies affected
what you do?
A
I manage to find some collaboration
that needs a simple model at the start

36. CAR
Pharm Res 19: 1788-1800, 2002

37. Q
Any unexpected surprises?
A
Pharmacophores opened collaborations
that still continue

38. hOCT1
Mol Pharmacol 63: 489-498, 2003

39. Q
Any other surprises?
A
The same set of compounds for closely
related enzymes could reveal structural
insights

40. CYP 3A4, 3A5, 3A7
Trends Pharmacol Sci 24: 161-166, 2003

41. 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

42. hERG
Drug Disc Today. 9: 276-285, 2004

43. Q
Any important implications?
A
Using phamacophores and other models
can reduce/ prevent need for animals

44. rbOCT2 and hOCT2
Drug Disc Today. 9: 276-285, 2004

45. Q
How have pharmacophores influenced your
work?
A
I worked a lot more on transporters and have
gone outside of ADME/Tox

46. hPepT1
Pharm Res, 22: 512-517, 2005

47. Q
What would surprise people about this work?
A
Most of it was performed without
NIH funding

48. OATPs
J Pharmacol Exp Ther 314:533-541 2005

49. Q
How have companies responded to models?
A
Some papers took a long time to see daylight

50. hERG
Pharm Res, 23: 1133-1143, 2006

51. Q
Why?
A
Projects died, people moved on, patents
that sort of thing lead to huge delays

52. CYP51
Drug Metab Dispos, 35: 493-500, 2007

53. Q
Did the models speed up science?
A
Yes we could cherry pick fewer compounds

54. P-gp
Drug Metab Dispos, 34: 1976-1984, 2006

55. 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

56. CYP3A4 MIC
Drug Metab Dispos, 35: 1466-1475, 2007

57. Q
How do you take something from the
past in new directions?
A
I keep looking for more collaborators
and more data

58. PXR agonists and antagonists
Mol Pharmacol, 72: 592-603, 2007

59. Q
Are there projects that surprised you?
A
Yes working on compounds with
anticancer activity provided a new outlet

60. P-gp substrates and anticancer compounds
J Med Chem, 51: 1242–1251, 2008

61. 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

62. Human and ciona LXR
J Steroid Biochem Mol Biol, 110:83-94, 2008

63. 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

64. PXR
BMC Evolutionary Biology, 8:103, 2008

65. 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

66. PEPT1 and PEPT2
Am J Resp Cell Mol Biol, 39: 536-542, 2008

67. Q
How has using multiple models been useful?
A
Gives more coverage of chemical space,
some models may fail
and others become useful

68. PXR
Drug Metab Dispos, 36:1689-97, 2008

69. 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

70. PXR antagonists
Mol Pharmacol, 74: 662-672, 2008

71. Q
Do you see cycling between targets
/ endpoints used for models?
A
I sort of alternate between PXR, transporters
and then miscellaneous uses

72. Immunoassay
Trends Pharmacol Sci, 30:138-47, 2009

73. Q
How have they helped educate others?
A
They have suggested the features
they need to look for or avoid in
new molecules

74. OCTN2
Pharm Res, 26:1890-1900, 2009

75. 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

76. ASBT
Mol Pharm, 6: 1591-1603, 2009

77. Q
As you move into new projects
pharmacophores go with you?
A
I try to find some use, not always possible
though

78. TB active compounds
Mol BioSyst, 6: 840-851, 2010

79. Q
How do you approach revisiting models?
A
Use new data to test them, expand and
Improve them

80. OCTN2
Mol Pharm, 7: 2120-2131, 2010

81. Q
Has your use of pharmacophores for
understanding evolution taken off?
A
We have used the approach exclusively
for nuclear hormone receptors

82. Pufferfish nuclear hormone receptors
BMC Biochem 12: 5, 2011

83. Q
What new uses have you envisioned?
A
Flipping the idea around to think of the
models to be of use for drug repurposing

84. OCTN2
Drug Disc Today, 16: 298-310, 2011

85. Q
Are there environmental consequences
of some models?
A
Models may help understand
how receptors evolved in response
to natural toxins in environment

86. Ciona VDR/PXR
Toxicon, 59:365-72, 2012

87. Q
How have you expanded the use?
A
Thinking of individual essential molecules
as providing insight into a target enzyme

88. TB in vivo essential metabolites
Pharm Res, 29: 2115-2127, 2012

89. Q
Where do you see potential growth areas?
A
Transporter substrates..

90. OCTN2 substrates
Mol Pharmaceutics, 9:905-913, 2012

91. Q
Why are transporters of interest?
A
Modeling has lagged behind that of P450s,
importance of increased screening in
pharma to understand drug interactions

92. MATE
J Pharmacol Exp Ther, 341: 743-755, 2012

93. Q
What is needed to facilitate this ?
A
More modelers working with groups
developing the data, methods to share
and test models collaboratively

94. NTCP
Mol Pharmaceutics, 10:1008-19, 2013

95. Q
What do you see holding you back or limits?
A
Time, in vitro testing of models

96. Antimalarials
Bioorg Med Chem Lett, 23: 1022, 2013

97. Q
Any new areas where shape is important?
A
Immunoassay cross reactivity – impacts
drugs of abuse and therapeutic drug
monitoring assay effectiveness

98. Methamphetamine and MDMA
Clin Toxicol, 51(2):83-91, 2013

99. Q
Any other considerations people need to
be aware of?
A
How you dispense liquids may impact
your data which will influence your model

100. EphB4 pharmacophores
PLOSONE, 8: e62325, 2013

101. Q
Any final words?
A
One pharmacophore is never enough

102. Credits
Collaborators on papers cited herein
Accelrys
With inspiration from
Charles Eames Design Q&A film

103. Contact
Collaborations in Chemistry
www.collabchem.com
ekinssean@yahoo.com