Selected project impacts from over a decade of using insights from computational chemistry Focus on heterocyclic rings in candidate drugs discovered at AstraZeneca/CVMD and the strategies used in their design. The case stories will include a wide variety of examples, such as (i) replacing unwanted functional groups like acids and esters with heterocyclic rings, (ii) using rings for geometrical reasons and (iii) using heterocyclic rings to fine-tune electrostatics to obtain improved properties. In most cases the key computational approach for designing candidate drugs has been the use of shape and electrostatic comparisons between molecules. The role of luck is also discussed.

1. Rings in (Candidate) Drugs – Case Stories
Jonas Boström, CVMD iMED, AstraZeneca R&D, Mölndal, Sweden
jonas.bostrom@astrazeneca.com

2. A Five Case Story Rollercoaster
key computational approach for designing candidate drugs often the use of shape and electrostatic comparisons between molecules
1) for (purely) geometrical reasons
2) replacing unwanted functional groups (acids and esters)
3) to fine-tune electrostatics for improved properties
2000
CB1
scaffold-hopping –>
only geometry matters 1
LXR
scaffold-hopping
and ”luck” 1
P2Y12
ester replacement
heterocycle 2
NOFI
acid bioisostere –
> heterocycle 2
now
”Matched-Pair
Project X”
heterocyclic electrostatics 
improved properties 3
Heterocyclic rings…

3. CB1
scaffold-hopping –>
only geometry matters?
CB1 antagonists – a “me-too” project
2000
now

4. Rimonabant (Sanofi-Aventis):
 a selective high-affinity CB1 inverse agonist
 inhibits food intake in rats, mice, marmosets and man
 was in clinical studies for treatment of obesity
Cannabis increases food intake  Marijuana users are often overweight  inverse agonist (or antagonist)?
No CB1 protein X-ray structure  ligand-based design
CB1 antagonists – a “me-too” project
Our scaffold-hopping strategy
Replace the pyrazole scaffold in Rimonabant with different heterocyclic rings:
thiazoles, pyrroles and pyrazines
Check chemical feasibility
Check shape-complementarity to the putative bioactive conformation of Rimonabant
Mini-libraries of 20 cpds/class were synthesized to evaluate the different classes.
Boström et al. “Scaffold hopping, synthesis and structure–activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: A novel series of
CB1 receptor antagonists”. Bioorganic and Medicinal Chemistry, 2007,15, 4077.

5. Shape-Based Scaffold-Hopping
All classes virtually identical to Rimonabant
Shape-overlays (ROCS). Tanimoto> 0.9
All central scaffolds “work”, and are electronically different – essential for geometrical reasons?
(compounds very lipophilic)
AZ-”pyrazines”
AZ-”pyrroles”
AZ-”thiazoles”
19 cpds synthesized
10 < 100nM
(4 < 10nM)
33 cpds synthesized
17 < 100nM
(4 < 10nM)
17 cpds synthesized
4 < 100nM
(2<10nM)
+ from the literature/patents
imidazoles, triazoles, ring-closures, etc

6. Withdrawal of marketing authorization for Rimnabant (FDA/EMEA). AZ Project stopped after candidate drug nomination.
Effect of AZ-”pyrazine” and Rimonabant on body-weight (BW) in cafeteria-diet, obese mice.
Cpd5e
CB1 Summary
AZ-”pyrazine”
AZ-”pyrazine”
any
heterocycle
?
“The function of the central scaffold is not to make any
direct interactions with the cannabinoid receptor, but
rather to place the substituted phenyl rings and the N-
carboxyamide fragments in an optimal 3D orientation”
Boström et al. “Scaffold hopping, synthesis and structure–activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: A novel series of CB1 receptor antagonists”.
Bioorganic and Medicinal Chemistry, 2007,15, 4077.

7. LXR
scaffold-hopping
and ”luck”
2015
LXR “Lucky” Scaffold-hopping
The Role of Conformational Analysis in the Design of LXR Agonists

8. “T0901317”
24 nM
“AZ HTS hit”
70 nM
A novel series of
potent nonsteroidal
LXR agonists
LXR “Lucky” Scaffold-hopping
Liver X Receptor (LXR) agonists for the treatment of atherosclerotic cardiovascular disease
Conformational ensembles OMEGA, shape-matching ROCS accessed via an interactive web-interface
The design of a novel series LXR agonists from a conformational analysis of two compounds:
Molecular
Alignments

9. LXR Scaffold-hopping
Systematic pair-wise shape comparison of low-energy conformation gave a few alignments
Conformational ensembles OMEGA, shape-matching ROCS accessed via an interactive web-interface
hydrophob
hydrophob
acceptor
acceptor
hydrophob
It seemed to make sense…
Tanimoto: 0.86
add one “H-bond acceptor”
Visual inspection of these favored the alignment which the N-substituted side-chains and the
phenyl rings (pharmacophores/SAR) are all in approximate coincidence.

10. Then came the LXR X-ray structure…
The right geometry (and potency)…but for the wrong reason…
Conformation was essentially correct, but the pose wasn’t
PDB: 1PQC

11. LXR X-ray structures were solved…
isothiazol-3(2H)-one 1,1-dioxides containing scaffold superior to HTS hit series
A novel series of
potent nonsteroidal
LXR agonists
“designed”
17 nM
lucky scaffold
hopping
expansion
virtually
identical
Project stopped after candidate drug nomination
“AZ HTS hit”
70 nM
Boström et al. “Do structurally
similar ligands bind in a similar
fashion?”. J.Med. Chem., 2006,
49, 6716.

12. P2Y12
ester replacement
heterocycle 2
P2Y12 – ethylester replacements

13.  Easy chemistry – library design
160 cpds with variation of substituents on pyridine and phenyl
SAR – affinity range for compounds binding/GTPgS
Zetterberg, Bach, Boström ”A novel series of piperazinyl-pyridine ureas as antagonists of the purinergic P2Y12 receptor” Bioorg. Med. Chem. Lett. 21 (2011) 2877–2881
SAR
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of
blood through the circulatory system. May cause stroke and sudden death.
HTS  several hits
Among the most interesting: the ”piperazinylpyridines” series
P2Y12 – Prevention of Thrombosis

14. Ethyl ester functionality a potential liability
• generally high in vivo clearance due to hydrolysis
P2Y12 – ethylester replacements
Can we replace the ester while retaining activity?
…and increase metabolic stability by replacing the ethyl ester with bioisosteres

15. P2Y12 – ethylester replacements
Non-cyclic ester replacements – inactive in P2Y12 binding and GTPgS

16. Design Strategy
Replace ethylester functionality by hydrolytically stable 5-membered heterocycle
Around 20 five-membered heterocyclic systems synthetically attainable evaluated.
Shape and electrostatics to classify similarity to ethyl ester
Heterocyclic Rings as Ethylester Replacements
“good”
+1
“mediocre”
+4
“bad”
+ a few
Ten compounds (structures shown) made and tested.
Bach, Boström, Zetterberg “5-Alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor”
Future Med. Chem., 2013, 5(17), 2037-2056

17. P2Y12 Results
Oxazoles a suitable replacement
shape and electrostatics (ItsElectric*)
* ItsElectric and EON (OpenEye) are based on the same
toolkit (ZAP) and theory (PB electrostatic potentials).

18. correctly suggests that 5-methyl-oxazole better than the 4-methyl oxazole
Conformations where possible ring-substitutents overlayed with the ethyl moiety selected
weak
H-bond
acceptor
strong
H-bond
acceptor
Shape & Electrostatic complementarities
vdW

19. P2Y12 Summary
The potential metabolic instability of ethyl esters was addressed by shape and electrostatics
rankings to select 5-membered heterocycles for synthesis.
Hydrolytically stable 5-methyl derivatives were identified as P2Y12 antagonists.
The physical nature of the shape and electrostatic similarity approach ensured that a non-obvious
substructure change could be incorporated to mimic the behavior of the ethyl ester functionality.
Not likely that other commonly used similarity measures (FPs, MCSS), would have predicted the
oxazole fragment as similar to the ethyl ester, let alone correctly suggesting that the 5-methyl-
oxazole was a better replacement for the ethyl ester than the 4-methyl oxazole.
The levels of clearance and bioavailability made the oxazoles series attractive compounds for
further development.
The ester subseries made it to the clinic – but lack of efficacy

20. …a P2Y12 X-ray structure was published (and PDB deposited) last year
P2Y12 Post-Summary

21. Where’s the H-bond donor?
Ethylester fits tightly, and no room for ”missing” waters.
SER-156 could adopt another rotamer (<4.0Å hbond) to carbonyl oxygen
No interaction for ether oxygen (making sense…)
Electron density quality
P2Y12 Post-Summary
PDB 4ntj
(Resolution 2.6Å)

22. “NOFI”
heterocyclics as carboxylic acid isosteres
Electrostatic
Similarities
2000
NOFI
acid bioisostere –
> heterocycle 2

23. Protein-protein interfaces provide an important class of drug targets receiving increased attention. The
typical design strategy usually involves large molecules (peptides and macrocycles)
A simplistic(!) view
of the mechanism
Novel Oral Fibrinolysis Inhibitors (NOFI)
Boström et al “Potent Fibrinolysis Inhibitor Discovered by Shape and Electrostatic Complementarity to the Drug Tranexamic Acid” J.Med.Chem. 2013, 56, 3273
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic

24. X-ray crystallography – structures known
pdb: 1ceb
(and 1cea)
Crystal structures of the recombinant Kringle 1 domain of human plasminogen in complexes with the
ligands EACA and TXA (Mathews et al. Biochemistry, 1996, 35, 2567–2576)
Fibrinolysis Inhibition

25. Project goal: identify novel compounds which can be given at lower doses and less frequently than
TXA, by improving some combination of the efficacy, bioavailability and clearance.
TXA and EACA are well-established clinical agents used to reduce blood-loss following surgery
and trauma and to treat heavy menstrual bleeding, mild haemophilia and certain forms of von
Willebrands disease
Tranexamic acid (TxA) EACA
Modest potency and non-optimal pharmacokinetic properties leading to inconvenient dosing (up to 6 g
per day). Associated side-effects are also nausea and vomiting.
This clearly limits their use and there is consequently an unmet need for new inhibitors of plasminogen
with a more convenient dosing and a more acceptable side-effect profile.
Lysine analoges:
Two Fibrinolysis Inhibitors on the Market

26. Zooming in on TXA in complex with the
recombinant kringle-1 domain of human
plasminogen …
prominent electrostatic features
zwitterionic...
pdb: 1ceb (TxA)
pdb: 1cea (EACA)
Shape-based approaches often successful in virtual screening. In this case not be sufficiently discriminatory due
to the simple molecular framework of the zwitterion TXA. This motivated us to compare electrostatic potentials

27. Low-throughput screening assay for testing putative blood clotting agents; select a small set of compounds
Shape-based screening not sufficiently discriminatory due to simple molecular framework of TXA
At the time, pre-filtering was a necessity (electrostatic calculations not fast enough)
“De-crapping” and visual inspection
Virtual Screen Strategy

28. Virtual Screening – Results
68 compounds screened – ‘only’ one hit
Remaining compounds selected were either weakly active or inactive.
VS
Clot-Lysis plasma assay 0.8 µMClot-Lysis plasma assay 3.1 µM
The potency of the lead compound 4-PIOL was found to be four times that of TXA, the current drug
widely used in the clinic. Surprising that such an active compound from such as a small set of
measurements was discovered.

29. Isoxazolone a bioisostere
Visual inspection of the hydrogen-bonding network in the ligand−protein complex indicates that 4-
PIOL and TXA bind in their zwitterionic forms (modelled in their neutral state).
The shape of the binding site is well-defined, with both ligands filling the binding site.
isoxazolone as a
carboxylic acid
bioisostere
(~5 times potent)
GABA 33nM
GABA 6nM
* Using ligand-based approach ROCS/EON
isoxazolone

30. ClotLys (Plasma): 0.8µM
pKa acid: 4.0
ClotLys (Plasma): 1.3µM
pKa acid: 4.1
ClotLys (Plasma): 4.0µM
pKa acid: 8.2
ClotLys (Plasma): 6.3µM
pKa acid: 7.0
ClotLys (Plasma): >100µM
pKa acid: 4.0
Tetrazole the most
common carboxylic
acid isostere, but is an
imperfect surrogate.
None more potent
Acquired and/or synthesized
heterocyclic compounds
Few similar compounds to 4-PIOL available internally and externally at the time*

31. Acquired and/or synthesized
heterocyclic compounds
ClotLys (Plasma): 0.8µM
pKa acid: 4.0
ClotLys (Plasma): 1.3µM
pKa acid: 4.1
ClotLys (Plasma): 4.0µM
pKa acid: 8.2
ClotLys (Plasma): 6.3µM
pKa acid: 7.0
ClotLys (Plasma): >100µM
pKa acid: 4.0
false positive
base acid
tetrazole shorter

32. Tetrazole vs isoxazolone
8.0Å (vs 9.3Å)
base acidtoo short

33. DMPK Profiling
The lipophilicity of 4-PIOL was determined to be low (logD < 0), an atypical liability.
Hydrophilicity can be disadvantageous, mainly due to poor cell permeability (Caco-2), resulting in
unfavorable DMPK characteristics in general and suggestive of difficulties with creating a
successful oral formulation
The pKa of the basic amines in TXA and 4- PIOL are similar (9.7 and 10.5), and that
the acid pKa’s are nearly identical (4.1 and 4.0).

34. Summary
• 4-PIOL was identified as a four-fold more potent fibrinolysis inhibitor than TXA using a low
throughput screen where the compound selection was made using computational
techniques.
• The key computational approach to our contribution for finding the right lead compound
was shape and electrostatic comparisons between molecules.
• It is clear that the computational approach described in the present work identified a non-
trivial bioisostere of TXA as a high quality lead for a subsequent lead optimization program.
• It is difficulty to accurately assigning correct ionization states to a large collection of
molecules, supporting our approach of modeling all compounds in their neutral state.
• 4-PIOL served as an excellent starting point for subsequent lead optimization.

35. Analogs to 4-PIOL selective against GABA-A, with good cell permeability and retained potency with respect
to plasminogen inhibition were designed, by means of two approaches, keeping the
graph/framework.
• A “methyl-scanning” exercise on 4-PIOL and
• molecular overlays of two structurally different series
Leading to the same observation:
substitution of the 2’-position increases GABA-A selectivity and improved cell permeability
Lead Optimization
Challenging synthetic chemistry issues were solved
Project stopped after candidate drug nomination.
“4-PIOL served as an excellent starting point for subsequent lead optimization”
* Concerns over commercial value especially after Lysteda (TxA in a sustained slower-release formulation) launch in US.

36. Molecular Matched-Pair Project X
”Matched-Pair Project X”
fine-tune heterocyclic electrostatics 
improved properties 3
https://twitter.com/jmedchem background from MMP oxadiazole paper:
Boström et al J. Med. Chem., 2012, 55, 1817

37. • “Molecules that differ only by a small structural change”
(remainder of the molecule is exactly the same).
For example
• The assumption underlying the matched-pair approach is that it is easier to predict
differences in the values of a property than it is to predict the value of the property
itself (one reason is cancellation of errors).
• The observation of an effect across several chemical series increases our confidence
that the effect is real -> general “rules of thumbs” -> future design
• One limitation is that it can only make predictions about structural features that have
precedent in the given assay.
What Are Molecular Matched-Pairs?
Prazosin Terazosin
Solubility: 1.1 mg/ml Solubility: 28.1 mg/ml

38. Oxadiazoles in an in-house AZ project
O
O N
N
R1R2
O
N N
O
R1R2
Binding Affinity: 80 nM
Log D: 3
Solubility: NA
HLM Clint: 20 µl/min/mg
hERG: 2 µM
Binding Affinity: 40 nM
Log D: 2
Solubility: 100 mM
HLM CLint: 10 µl/min/mg
hERG: 10 µM
1,3,4-oxadiazoles showed better properties than 1,2,4-oxadiazoles
in terms of lipophilicity, solubility, HLM Clint and hERG
Goal: to develop a better understanding for the generality of the observed effects, as
well as if possible rationalize the effect.
1,3,4-oxadiazoles1,2,4-oxadiazoles

39. Oxadiazoles
are five-membered heterocycles containing two carbons, two nitrogens and one oxygen atom
and they exist in several different regioisomeric forms
R' O
N N
R''
R' N
O N
R''
R'
N N
O
R''
R' N
N O
R''
1,2,4-oxadiazoles
1,3,4-oxadiazole
1,2,5-oxadiazole
CSD: NAXDIZ
CSD: ZZZTQC01
Side chains (R-groups) will have the same exit vector for 1,2,4 and 1,3,4 regioisomers:
same overall shape
(but the 1,2,5 regioisomers differs)

40. Year
Frequencyofoccurrenceofoxadiazoles
inPharmaceuticalPreparations
Oxadiazoles in drug projects
Oxadiazole rings are used in drug discovery programs for different purposes
• contributing to the binding interactions with the target.
• modulates molecular properties through its position on the periphery of the molecule
• oxadiazoles has been used as replacements for carbonyl containing compounds (esters, carbamates, hydroxamic esters)
• as linker to orient its substituents appropriatly.
N
S
N
H
N
N
O
O
O
O
N
N
OH
ONO
N
F
1 (zibotentan) 2 (ataluren)
Structures of oxadiazole compounds in late stage clinical development or launched
F
N
H
O
N
N
O
OH
N
H
O
NN
O
3 (raltegravir)

41. Oxadiazole data set
Using query-specific matched-pair tool 150 pairs.
The compounds essentially show the same characteristics as compounds with typical drug-like properties.
The data set covers molecules with different ionization states at physological pH;
and several structural series; ~25 clusters. ClogP
H-bond don+acc
MW

42. Check differences in lipophilicity
ordered exp. logD for the 148 matched-pairs
1,3,4-oxadiazole are systematically less lipophilic than their 1,2,4-oxadiazole partner by one log unit
R' O
N N
R''R' N
N O
R''
1,2,4-oxadiazoles 1,3,4-oxadiazole
The median logD value for the 1,2,4-isomers
is 4.4, whereas it is 3.2 for the 1,3,4-isomers.
y = 0.99 + 1.06*x
r2 = 0.97
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817

43. Matched Pairs Consequences
Lipophilicity is a cardinal property in drug discovery.
It generally affects many other properties relevant in lead optimization.
How would the difference in lipophilicity between the oxadiazole regioisomers
impact other molecular properties?
We investigated for example:
 Solubility
 hERG (and pKa)
 CYP inhibition
 HLM CLint
Desiredproperty
Lipophilicity/undesired property
1
2
3
?

44. Impact on solubility (subset of 55 pairs)
Lipophilicity can influence many other molecular properties, and perhaps the most obvious
connection exists between lipophilicity and solubility.
R2=0.4
N=116
In general the 1,3,4-oxadiazole is more soluble
than the 1,2,4-oxadiazole partner
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817

45. In addition, the 1,3,4-oxadiazoles generally show better metabolic stability, in terms of lower
HLM CLint values (34 matched-pairs).
Impact on CYP inhibition
For various CYP enzymes the inhibitory potency of the less polar 1,2,4-oxadiazole derivatives is typically
more pronounced than that of the more polar 1,3,4-conterparts; this is particularly true for CYP3A4
(recognizing lipophilic substrates) and CYP1A2 (recognizing planar heterocycles).
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817

46. Inhibition of the hERG channel can trigger Torsades de Pointes and arrhythmia
One design strategy to reduce hERG inhibition is to decrease lipophilicity.
In the majority of cases (N=11), the less lipophilic isomer (1,3,4) is also less potent at hERG.
All matched pairs in this subset have a basic functionality near the oxadiazole unit.
There’s little or no change in pKa upon switching between the regioisomers. That is, the
regioisomers do not have a significant effect on the basicity of the nearby groups.
Impact on hERG
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817

47. Using electrostatics to rationalize
Why are 1,3,4-oxadiazole less lipophilic? Ask your MedChemists (none knew) and calculate…
Dipole calculations at B3LYP/6-31G**. Experimental data confirms.
Kenny P. et al. J. Med. Chem. 2008, 51, 3720–3730, and Kenny P J. Chem. Soc. Perkin Trans 2 1994, 199-202
1,3,4-oxadiazole show significantly larger dipoles than their 1,2,4-oxadiazole partner
The greater the dipole the greater polarity.
N
ON
O
N N
Minimized molecular electrostatic potential (Vmin) has been shown to be an effective predictor
of the of hydrogen bond acceptors
- hydrogen bond acceptor strength changes and moves around

48. Other (unexpectedly) large differences
 thiadiazole regioisomers
 THF vs furan
We have for example investigated:

49. Thiadiazoles regioisomeric pairs
Calculated electrostatics show analogous differences to oxadiazole regioisomers
(3.7 vs 2.5D) although the difference is slightly smaller (3.3 vs 2.6D).
In thiadiazoles the oxadiazole oxygen atom is ‘replaced’ by a sulfur atom
Prediction: a 1:1 relationship between regioisomeric pairs, and that the 1,3,4-
thiadiazoles is less lipophilic than 1,2,4 regioisomers.
N
SN
S
N N
3.3 D
2.6 D
level of theory: HF/3-21G*
exit vectors
differ somewhat

50. 0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6 7 8
explogD
1,2,4-thiadiazoles
exp logD
1,3,4-thiadiazoles
Differences in lipophilicity
1,3,4-thiadiazole are in general less lipophilic than their 1,2,4-thiadiazole partner
R' S
N N
R''R' N
N S
R''
1,2,4-oxadiazoles 1,3,4-oxadiazole
R2=0.92
logD
The median logD value for the 1,2,4-isomers
is 3.2, whereas it is 2.3 for the 1,3,4-isomers.
N = 33
ordered exp. logD for the 80 compounds
1,2,4-thiadiazoles 1,3,4-thiadiazoles

51. Alpha-blocker
Solubility: 1.1 mg/ml
Log D (shake-flask): 1.8
ACDlogD: 0.0
clogP: 2.0
Alpha-blocker
Solubility: 28.1 mg/ml
Log D (shake-flask): 0.9
ACDlogD: -1.0
clogP: 2.2
A “me-too” observation: furan vs THF
Modification of the hybridization state of carbon atoms can be useful to control molecular properties.
Prazosin (Minipress™) – Terazosin (Hytrin™) serves as a matched-pair “me-too” example.*
* Water solubility for Terazosin increases significantly when going from furan to THF. As a result, improved
bioavailability (90% vs 57%) and half-life (2–3 times) afford longer duration of action, and allow once-daily
administration. In addition, there is a safety concern associated with furans, since they are often anticipated to be
carcinogentic in humans.
Giordanetto, Boström and Tyrchan “Follow-on drugs: how far should chemists look?” Drug Discovery Today, 2011, 16 (15-16),722-732. (doi:10.1016/j.drudis.2011.05.011)
Prazosin
US Reg Date: 1976-06-23
Terazosin
US Reg Date: 1987-08-07

52. Furan vs tetrahydrofurans: Dsolubility
average pSolubility: 4.0 (100µM)average pSolubility: 4.7 (20µM)
D pSol: 0.7
A data set of 50 matched-pairs – measure aqueous solubility for the 100 compounds
The THF containing compound is more soluble in 85% of the matched-pairs.
THF
pSolubility
pSolubility (furan)
The observered difference in solublity for furan/THF pairs seems to be general.
R R

53. Possible rationale for differences
Larger dipole for THF than furan – the greater the dipole the greater polarity.
The aromaticity in furan obviously makes it different from ethers, especially compared to more strained systems like oxatanes and
tetrahydrofurans. Consequently tetrahydrofurans seem to be less lipophilic than their open-chain ether partners.
Furan:
0.6 Debye
THF:
1.7 Debye
FURAOX LIBVIC
Different geometries – “escaping flatland”
two matched-pairs found in CSD
A forgotten furan-bioisoster? Furan-to-Thiophene/Benzene is way more frequent than furan-to-THF.

54. Matched-Pairs Summary
 It can be very powerful to use molecular matched-pairs in drug design.
• Intuitive, interpretable and can provide data-driven, interpretable guidelines for design/analysis
• Can extract tacit knowledge from accumulated data beyond series, projects and departments
 Analyzing 1,2,4- and 1,3,4-oxadiazole regioisomers revealed systematic trends
 the 1,3,4-oxadiazole isomer show an order of magnitude of lower logD, compared to the 1,2,4
 the favorable effect is also observed in increased aqueous solubility, lower HLM Clint and hERG.
 The distinct profile difference is likely due to their different charge distributions.
 Methodology can be used to generalize other important properties used for decision-making.
 thiadiazoles regioisomers, THF vs furan.
 direct impact in in-house AZ projects.

55. Thanks to all my colleagues!
key computational approach for designing candidate drugs often the use of shape and electrostatic comparisons between molecules
1) for (purely) geometrical reasons
2) replacing unwanted functional groups (acids and esters)
3) to fine-tune electrostatics for improved properties
2000
CB1
scaffold-hopping –>
only geometry matters 1
LXR
scaffold-hopping
and ”luck” 1
P2Y12
ester replacement
heterocycle 2
NOFI
acid bioisostere –
> heterocycle 2
now
”Matched-Pair
Project X”
heterocyclic electrostatics 
improved properties 3
Heterocyclic systems needs special attention – a large number of combinations