Fat, Drunk, and Stupid Talk

1. “Fat, Drunk, and Stupid is No Way
to Go through Life”:
(Re)Thinking Fragment Libraries
Edward R. Zartler, Ph.D
Quantum Tessera Consulting
And
Chris Swain, Ph.D
Cambridge MedChem Consulting

2. ENC 2004
2

3. The “Rule” of 3
• MW< 300 (< 21 HAC)
• H-BondDonor< 3
• H-BondAcceptor < 3
• cLOGP< 3
Also suggested:
• # RotBonds< 3
• PSA< 60 (hey, it’s a multiple of three!)
www.quantumtessera.com 3
Drug Discovery Today (2003) 8:876

4. Beware multiple qualifiers.
“We carried out an analysis of a diverse set of
fragment hits that were identified against a range of
targets. The study indicated that such hits seem to
obey, on average, a ‘Rule of Three’…”
• One paragraph before, they mention only kinases
and proteases, so… is the Ro3 based upon only
these target types? Seems so…
• If so, those who dogmatically use it are being
stupid unenlightened, especially if they are
screening proteases/kinases.
“The study indicated that such hits seem to obey, on
average…”
www.quantumtessera.com 4

5. Properties of Published Fragments
Slide from C. Swain 5
450 fragments against 67 targets
40% contain ionizable group

6. Because Animal House is full of Wisdom
6
MW/HAC cLogP
Do
FBHG

7. Fat
• Arbitrary cutoffs are arbitrary and thus do not
involve thinking
• According to a poll at the Practical Fragments
blog, nobody uses fragments >20 HA
• Does these rules apply to Fsp3-enriched
libraries?
• Rules should be applied when they are fully
understood.
www.quantumtessera.com 7

8. Drunk
• cLogP: the partitioning of an “un-ionized”
compound into two immiscible solvents at
equilibrium.
Typically, water and alcohol (n-octanol).
– 1.4 logP units is added during optimization
– Is solubility a better metric to track?
www.quantumtessera.com 8
J. Med. Chem., 2013, 56:2478

9. State of the Art: Solubility
• Experimentally Measure, and first!
9
E.R. Zartler et al. (2013) Drug Discovery World, Winter 2012/2013
SolubleIn-Soluble

10. Stupid
• Dogma is static, does not take into account
reality
• Every library has rules they apply:
– RO3 being the main one.
• Everything should be done with a purpose
www.quantumtessera.com 10

11. What do medChemists think they need?
• Molecules with activity towards Target
– Selectivity (Bonus!)
– Selection of screen is key (Short Course)
• Novel Scaffolds
– Is there such a thing as novelty in FBHG?
• Chemical space to work in
– Every atom is sacred
• SAR
– I like it early, helps to confirm screen hits
– Many people will generate it later

12. 12
MedChem is All the Same
DKd DDG
10x 1.37
100x 2.73
1000x 4.2
DG=-RTlnKd
R=1.99 cal/Kmol
RT=0.6 kcal/mol at 300K
10x = 1.4kCal=1 Hydrogen Bond
Ideally, 0 atoms have to be added
Realistically, 3 atoms give10x (LEAN of 0.3)
The difference between 100mM and 10mM is
onedifferent atom, or one ideal atom, or three good ones.
It’s all Thermodynamics
1mM->1nM is 18 good atoms more (31 atoms at 1nM)
1mM->1nM is 9 good atoms more (35 atoms at 1nM)
Beware the Sauron Atom!
http://practicalfragments.blogspot.com/2012/11/atoms-are-like-apples.html

13. Cascading Fragment Libraries
13
Binding Assay 1 (100 cpds)
Binding Assay 2 (1000 cpds)
Biochemical Assay (>10,000 Cpds)

14. The Role of 19F
• 19F is exciting and a personal fetish
– See Brad Jordan’s talk from FBLD last year!
• Where/when would you use it?
• Aliphatic libraries because NMR-focused
libraries like to avoid a lot of aliphatics?
• Target focused screening 19F-protein
www.quantumtessera.com 14

15. N
N
S
2D Fragments
• Planar fragments seemed to be adored by certain classes of
targets, e.g. kinases.
• Planar fragments explore “chemical space” efficiently, but what
about “vector space”?
– Bond rotations and global motion float, interaction sites are still
relatively limited.
• Are we like Khan, do we think two-dimensionally to a fault?
15
N N
S

16. 3D Fragments
• Seem to be loved by certain target classes
• Sample chemical space inefficiently
• Are able to sample vector space to varying degrees.
• 3D spiro compounds vs. rotatable bonds
• Rotatable bonds pay an entropy cost, but access more vector
space. More rotation, more entropy, more vector space…
N
N

17. 3D fragments expectations
• If you have structural data (X-ray), 3D fragments should only
be used as a tool.
• If you don’t have structural data, the fragments should be part
of the final molecule, or you at least need to have a strategy for
combining it with other fragment hits.
• 3D libraries are bigger (in general) than 2D fragments…so you
start with fewer addable atoms.
• A wholy 3D fragment library would have to be FAR larger than
an equivalent 2D library.
17
http://3dfrag.org/

18. 2D vs. 3D Fragments
• Is this an either/or proposition?
– Shouldn’t be…like anything its compromise
• The ideal library would be:
– Primarily 2D fragments (very planar) “Chemical Space”
– Large enough to cover sufficient chemistry space
– Built-in SAR to develop hypotheses.
– Small portion of 3D fragments, but related to the 2D members
“Vector Space”
– Rapidly accessible follow up fragments for SAR
18

19. “3D-arity” of Commercial Libraries
www.quantumtessera.com 19

20. Principal Moment of Inertia (PMI)
Better 3D Metric?
20
Iota
Lead-Like:CCG
WIREs Comput Mol Sci 2012, 2: 868–885