SORD and Lost Chemistry
Dick WifeSORD BV
SORD Objectives
It is not our job to discover new drugs
It is our job to make this process easier
ChemistryScheikunde (Dutch): the ability to cut
Sensible questions:Is this product new?Is this reaction new?Is there a related precedent?What sort of reagent(s) and
reaction conditions?
Choices
PublicationNote, Letter,
Communication
PublicationNote, Letter,
Communication
Publication/Thesis
ThesisThesis
PublicationFull paper
PublicationFull paper
? ?
Thesis/Dissertation
AbbreviationsIntroductionResults & DiscussionExperimental +/- 95 reactionsReferences/NotesSupporting Data
“Lost Chemistry”
Only published as a Note, Communication, Letter, etc.Unpublished = Unpublishable? Not enough story for a publication…Reputation: ABCZ/loose endsNot written in English
It really depends on who you are and what you are looking for…
Source Languages
Analysis: country of origin of 300k “drug-like” compounds
SOR Database
Reaction Scheme (RS) Experimental (EX)
Fields:Reagent(s)Solvents(s)YieldMPOptical Rotation
PDF-EX
Spectral data
Excerption Rules
Reaction Scheme: only reactants and productsReagent: needed for the reaction but does not show up in the productSteps: 1,2, etc. if no intermediate is isolatedProduct: if isolated and characterizedNo failed reactions
Time Line 05/2011
Hard copy Digital/E-born E-born
0.2% 14.9% 48.8% 35.1%
Source Reaction Data
15 May 2011 Theses Groups Univ.1941 368 138
Europe 73% North America 21% Asia 5%
SOR Database
Selected Life Science ChemistryRS & EX fully searchablePDF-EX (>90% with spectral data)French/German English EX translationCharacterized reaction products onlyFree access to academic collaborators
Databases and Content
de Laet, A.; Hehenkamp, J. J.; Wife, R. L. Finding Drug Candidates in Lost/Emerging Chemistry. J. Heterocycl. Chem. 2000, 37, 669–674. (SORT&gen)
G.W. Bemis and M.A. Murko J. Med. Chem. 42 (1999), : 50 scaffolds account for 50% of known drug molecules
Commercial Database with 9 million organic compounds
450k (5%) “drug-like” organic compounds
Drug Discovery & Chemical Space (1)
It may be comforting to know that for every possible disease, now and in the future,
a drug exists in Chemical Space
Real/Virtual Chemistry!
Drug Discovery & Chemical Space (2)Intuition
• Rational Design• High Throughput Screening (HTS)• Combinatorial Chemistry (CC)• Targeted Libraries
Kalliokoski, Tuomo. Accelerating Three-Dimensional Virtual Screening: NewSoftware and Approaches for Computer-Aided Drug Discovery. Publicationsof the University of Eastern Finland. Dissertations in Health Sciences, 22. 2010
Drug Discovery in silico tools
• Compound selection• Compound solubility• ADME tox• Further chemistry
What does a drug look like?
NH
NH
OH
O
NH
O
NH
O
NH
OHO
NH
NH2
O
NH O
NH
NH
O
OOH
S
S
NHO
NH
O
NH
O NH
ONH2
OH
O
NH2
O
NHO
NH2
Somatostatin, Octreotide ($ 1 billion 2009)
NH2
Amphetamine ($ 1 billion 2009)
Top 200 drugs 2006
Discrete organic structures 162
Antibodies, vaccines, etc. 38
MW < 200
N
OH
O
N NH NH2
NH NH NH2
NO
O
NH2OH
O
OH
NH
O
OH
O
OH
NH2
OH
O OH
NH2
OH
NH2
H ONO
H
NH2
O
N
N
OH
N+ O
-
O NH2
OH
O
OHNH2
OH
O
O
OO
OH
H OH
ON+
O
O- N
NN
NN
O
ONH2
Top drugs
Atovastatin (Lipitor, Pfizer $ 13.3 billion 2006)
N OH
OOHOH
F
O
NH
Statins (1)
Atovastatin (Lipitor, Pfizer $ 13.3 billion 2006)N OH
OOHOH
F
O
NH
N
N
F
N
S OO
OH OH
OH
O
Rosuvastatin (Crestor, AZ $ 2.1 billion 2006)
O
OH
H
OOH
OH
OHO
Pravastatin (Pravachol, BMS $ 1.2 billion 2006)
Carreira & Seebach (2003)
O
OOOH H
H
OO
O
OHB
H
H
H HO
O
OHOHNa
+
+
Indole chemistry
N
H
H
H
N
H
H
Reactant 523 Product 112
Product 126
N
H
HN
H
H
H
N
H
H
H
N
H
H
NH
+
O
N
NH
OH
N
NH
+ N
O
O
NH
O
O
NH
NH
+I O
F F
F NH
F
F
F
Ley
Joule
Togni
Ley
Joule
Dumy
N
H
HN
H
H
H
N
O
O
O
O
+NH
O
NH
NH
O
O
O
OO
+
NH
NH
O O
O
OO
NH
+ OH +O
O
Cl
Cl NH
O
O
O
N+
N+
O-
O
O-
O
O NHO
O
+ NH
Br
N+
NH
N
NH
O-
O
O
O
OHO
O
Br
Marcantoni
Echavarren
N
H
HN
H
H
H
NH
+N
+
O-
O
NN
+
NH
O-
O
N
NH
+OH
NH
O
BMS/HIV 2011
N
N
N
O
O
O
BMS-216
N N
N
N
O
O
O
O
BMS-378806
N N
N
N
O
O
O
O
O
N N
N
N
O
O
O
O
N
N
NO P
O
O
O
O O
O
N+
BMS-488043 BMS-663068
Indole chemistry/BMS/HIV
NH
+ OH +O
O
Cl
Cl NH
O
O
O
N
N
N
O
O
O
BMS-216
Joule
BMS/HIV
N N
N
N
O
O
O
O
O BMS-488043
N+
NO
-
O
Cl
+NO
O+ H H N
NH
Cl
NH
+ OH +O
O
Cl
Cl NH
O
O
O
Joule
Joule
Tetrazoles
NN
NNH
N
N
Cl
OH
NN
NNH
N
N
O
N
OHO
O
N
NNH
N
N
NNH
NN
N
OH
O
O N
N
O
O
O
O
O
OH
N
NNH
N
N
S
O OH
S
N N
NN
NHO
O
S
S
NH2
O
OOH
O
Hypertension 2009 $ billion
2.135 0.767 3.912
1.705 1.533
Tetrazoles
N
NNH
N
NN
N NH
NS
N+
N N
NN
N
NNH
N
N
NH
S
Al+
+Neier
Benzimidazoles
NH
N
A
S
N
NH
NH
O
O
NH
NO
N
NH
O
NH
N
O
S
O
N O
N
NH
S
O
N
O
O
NH
NS
O
N
O
F
F
F
N
NH
S
OOF
F
N
O O
N
NNH
NN
N
OH
O
O
N
N OH
OO
N
NNH
NH2
NH
O
OH
NN
N
N
Benzimidazole
Buschauer
Batey
Black
N
NH
S
O
Cl
O
N
N
S
O
O
+
N N
NH
O
O
I
O
N
N
N
O
O
O
N+
NH
O
O
O
O
O
NH2 NH2N
NH
O
O
+
Reagent DB (2764)
Reaction Reagent (Similar) reactions
Hermann-Beller palladacycle
O O
P Pd+
OO
PPd+
Inspiration!
Hermann-Beller palladacycle
Tietze
N
O
O
O
N
IN
O
O
N
O
+
O O
P Pd+
OO
PPd+
O
Br
OO
O
O O O
O
OO
O
Br
O
H
H
O
O
H
HH
Greaney
More inspiration!
Hermann-Beller palladacycle
Tietze
O O
P Pd+
OO
PPd+
N
O
O
O
Br
N
O
O O
H
N
O
O
Br
N
O
O
H
O O
Br BrH H
H H
O O
H H
HH
HH
Grubbs 2 catalystO
O+Blechert
N
O O
N
O
OCraig
O
I
O
I
Lautens
Conclusions
• All-thesis excerpted so surprises too• Will contain trivial reactions• Intelligent queries deliver results• Graphics driven (needs improvement)• As diverse as possible• A supplement to bigger databases
For Licensing and Sales information please contact ACD/Labs
To become an academic collaborator please contact SORD