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BioSolve IT GmbH • An der Ziegelei 75 • 53757 Sankt Augustin • Germanywww.biosolveit.de
BioSolveITBiology Problems Solved using Information Technology
FlexXpast, present, and planned
technological advancementsChristian Lemmen
Christian Lemmen @ ACS, August 23rd 2004 2 © B
ioS
olve
IT G
mbH
the developers of FlexX
Overview
Past
The FlexX-basics
Present
FlexX-Pharm, FlexE
Docking Database (DDB), Major Release 2.0
Planned
Isosteric Replacement
FlexX-Scan
Christian Lemmen @ ACS, August 23rd 2004 3 © B
ioS
olve
IT G
mbH
the developers of FlexX
PastBrief FlexX-History
1993 Matthias Rarey started developing FlexX
1995 first presentation at the ISMB-conference1
1996 first JCAMD-paper2
1998 first marketed internationally
1999 the sibling program FlexS followed
2001 spin-off founded
2004 over 100 commercial customers world-wide
[1] Rarey et al. In Proceedings 3rd ISMB (1996), 300–308[2] Rarey et al. JCAMD (1996)10, 41–54
Christian Lemmen @ ACS, August 23rd 2004 4 © B
ioS
olve
IT G
mbH
the developers of FlexX
PastThe FlexX-Basics
Incremental construction algorithmBase selectionBase placementComplex construction
About 30 sec per compound
70% of benchmark datareasonably placed3
Numerous successful virtual screening applications4
[3] Kramer et al. Proteins (1999) 37:228-241[4] Stahl et al. In Bioinformatics (2001)2, 137-170
Christian Lemmen @ ACS, August 23rd 2004 5 © B
ioS
olve
IT G
mbH
the developers of FlexX
FlexX-Features
PVM parallel comp.
CombiLib docking5
Considering waters (the particle concept)6
sophisticated numerical optimization
Past
N
NO O
R1
R3 R2
H
R1 R2 R3
Ca
R2a
R3a
R1aR1b
on 10 CombiLibs (5k ..16M cpds)10 fold - 100 fold savings
[5] Rarey et al. PDDD (2000)20, 63–81[6] Rarey et al. Proteins (1999)34, 17–28
Christian Lemmen @ ACS, August 23rd 2004 6 © B
ioS
olve
IT G
mbH
the developers of FlexX
FlexX-Pharm
Pharmacophoreguideddocking7
Faster screening andimproved solutions
Successful applications*
Present
Ligand
Receptor
interaction constraint:
spatial constraint:
[7] Hindle et al. JCAMD (2002)16, 129-149[*] Lyne et al. JMC 47 (2004) 1962ff[8] Hindle et al. In 14th EuroQSAR (2003), 135-139 0
10
20
30
40
50
60
1000 2000 3000 4000
1%
~ 0.5 millioncompounds9
101cpds
FLEXX-PHARM
FLEXX
Christian Lemmen @ ACS, August 23rd 2004 7 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentFlexE
Protein flexibilityproton configurationside-chain conformationshort loop movement
The ensemble approachsimultaneously considermultiple active site copies
Ensemble
[9] Claußen et al. JMB (2001)308, 377-395
Christian Lemmen @ ACS, August 23rd 2004 8 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentFlexE
Protein flexibilityproton configurationside-chain conformationshort loop movement
The ensemble approachsimultaneously considermultiple active site copies
United Protein Structure
[9] Claußen et al. JMB (2001)308, 377-395
Christian Lemmen @ ACS, August 23rd 2004 9 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentFlexE
Protein flexibilityproton configurationside-chain conformationshort loop movement
The ensemble approachsimultaneously considermultiple active site copies
[9] Claußen et al. JMB (2001)308, 377-395
Christian Lemmen @ ACS, August 23rd 2004 10 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentFlexE
Protein flexibilityproton configurationside-chain conformationshort loop movement
The ensemble approachsimultaneously considermultiple active site copies
[9] Claußen et al. JMB (2001)308, 377-395
Christian Lemmen @ ACS, August 23rd 2004 11 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Our Database Connection
how we usually describe ‘the problem’
©C
amille
Pis
sarro
Christian Lemmen @ ACS, August 23rd 2004 12 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Our Database Connection
how we usually describe ‘the problem’
... we propose to get a little more organized
©C
amille
Pis
sarro
Christian Lemmen @ ACS, August 23rd 2004 13 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Docking Database
Purposestructured storage of all solutions
emphasis on multiple solutionsno parsing temporary (mass) storage
FLEXX/DOCKING> listall 1+---+-------+-------+------+------+------+-----+------+------+------+------+-|No.|Total |Match- |Lipo- |Ambig-|Clash-|Rot- |RMS- |Simil.|#Match|Avg. |M| |Score |Score |Score |Score |Score |Score|Value |Index | |Volume|V+---+-------+-------+------+------+------+-----+------+------+------+------+-| 1|-36.876|-39.970|-2.015|-4.150| 1.059|2.800| 3.284| 1.844| 7| 0.254| +---+-------+-------+------+------+------+-----+------+------+------+------+-SELECTED MATCHES: 121p -- 121p_min+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+|No.|Lig.|Lig.|Ligand |Rec.|Rec.|Rec. |Rec. |Receptor |Opt. |Chg. || |Atom|ANo.|IA-Type |Atom|AA |Chain|AANo |IA-Type |Engy.| |+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+| 1|O1G | 2|h_acc | N |GLY | | 13 |h_don |-4.70|-0.00|| 1|O2G | 3|metal_acc |MG | MG | | 168 |metal |-4.70|-1.20|| 1|O3G | 4|h_acc | NZ |LYS | | 16 |h_don |-4.70|-0.60|| 1|O3G | 4|h_acc | N |GLY | | 15 |h_don |-4.70|-0.00|| 1|O2B | 8|metal_acc |MG | MG | | 168 |metal |-4.70|-1.00|| 1|O3G | 4|h_acc | N |LYS | | 16 |h_don |-4.70|-0.00|| 1|O2G | 3|h_acc | N |SER | | 17 |h_don |-4.70|-0.00|+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+
Christian Lemmen @ ACS, August 23rd 2004 14 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Docking Database
Purposestructured storage of all solutions
emphasis on multiple solutionsno parsing temporary (mass) storage
FLEXX/DOCKING> listall 1+---+-------+-------+------+------+------+-----+------+------+------+------+-|No.|Total |Match- |Lipo- |Ambig-|Clash-|Rot- |RMS- |Simil.|#Match|Avg. |M| |Score |Score |Score |Score |Score |Score|Value |Index | |Volume|V+---+-------+-------+------+------+------+-----+------+------+------+------+-| 1|-36.876|-39.970|-2.015|-4.150| 1.059|2.800| 3.284| 1.844| 7| 0.254| +---+-------+-------+------+------+------+-----+------+------+------+------+-SELECTED MATCHES: 121p -- 121p_min+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+|No.|Lig.|Lig.|Ligand |Rec.|Rec.|Rec. |Rec. |Receptor |Opt. |Chg. || |Atom|ANo.|IA-Type |Atom|AA |Chain|AANo |IA-Type |Engy.| |+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+| 1|O1G | 2|h_acc | N |GLY | | 13 |h_don |-4.70|-0.00|| 1|O2G | 3|metal_acc |MG | MG | | 168 |metal |-4.70|-1.20|| 1|O3G | 4|h_acc | NZ |LYS | | 16 |h_don |-4.70|-0.60|| 1|O3G | 4|h_acc | N |GLY | | 15 |h_don |-4.70|-0.00|| 1|O2B | 8|metal_acc |MG | MG | | 168 |metal |-4.70|-1.00|| 1|O3G | 4|h_acc | N |LYS | | 16 |h_don |-4.70|-0.00|| 1|O2G | 3|h_acc | N |SER | | 17 |h_don |-4.70|-0.00|+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+
Christian Lemmen @ ACS, August 23rd 2004 15 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Docking Database
Purposestructured storage of all solutions
emphasis on multiple solutionsno parsing temporary (mass) storage
Benefits:re-scoring
filtering on-the-flytarget-specific ranking
FLEXX/DOCKING> listall 1+---+-------+-------+------+------+------+-----+------+------+------+------+-|No.|Total |Match- |Lipo- |Ambig-|Clash-|Rot- |RMS- |Simil.|#Match|Avg. |M| |Score |Score |Score |Score |Score |Score|Value |Index | |Volume|V+---+-------+-------+------+------+------+-----+------+------+------+------+-| 1|-36.876|-39.970|-2.015|-4.150| 1.059|2.800| 3.284| 1.844| 7| 0.254| +---+-------+-------+------+------+------+-----+------+------+------+------+-SELECTED MATCHES: 121p -- 121p_min+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+|No.|Lig.|Lig.|Ligand |Rec.|Rec.|Rec. |Rec. |Receptor |Opt. |Chg. || |Atom|ANo.|IA-Type |Atom|AA |Chain|AANo |IA-Type |Engy.| |+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+| 1|O1G | 2|h_acc | N |GLY | | 13 |h_don |-4.70|-0.00|| 1|O2G | 3|metal_acc |MG | MG | | 168 |metal |-4.70|-1.20|| 1|O3G | 4|h_acc | NZ |LYS | | 16 |h_don |-4.70|-0.60|| 1|O3G | 4|h_acc | N |GLY | | 15 |h_don |-4.70|-0.00|| 1|O2B | 8|metal_acc |MG | MG | | 168 |metal |-4.70|-1.00|| 1|O3G | 4|h_acc | N |LYS | | 16 |h_don |-4.70|-0.00|| 1|O2G | 3|h_acc | N |SER | | 17 |h_don |-4.70|-0.00|+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+
Christian Lemmen @ ACS, August 23rd 2004 16 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Docking Database
Purposestructured storage of all solutions
emphasis on multiple solutionsno parsing temporary (mass) storage
Benefits:re-scoring
filtering on-the-flytarget-specific ranking
generate anaccessible haystack
FLEXX/DOCKING> listall 1+---+-------+-------+------+------+------+-----+------+------+------+------+-|No.|Total |Match- |Lipo- |Ambig-|Clash-|Rot- |RMS- |Simil.|#Match|Avg. |M| |Score |Score |Score |Score |Score |Score|Value |Index | |Volume|V+---+-------+-------+------+------+------+-----+------+------+------+------+-| 1|-36.876|-39.970|-2.015|-4.150| 1.059|2.800| 3.284| 1.844| 7| 0.254| +---+-------+-------+------+------+------+-----+------+------+------+------+-SELECTED MATCHES: 121p -- 121p_min+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+|No.|Lig.|Lig.|Ligand |Rec.|Rec.|Rec. |Rec. |Receptor |Opt. |Chg. || |Atom|ANo.|IA-Type |Atom|AA |Chain|AANo |IA-Type |Engy.| |+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+| 1|O1G | 2|h_acc | N |GLY | | 13 |h_don |-4.70|-0.00|| 1|O2G | 3|metal_acc |MG | MG | | 168 |metal |-4.70|-1.20|| 1|O3G | 4|h_acc | NZ |LYS | | 16 |h_don |-4.70|-0.60|| 1|O3G | 4|h_acc | N |GLY | | 15 |h_don |-4.70|-0.00|| 1|O2B | 8|metal_acc |MG | MG | | 168 |metal |-4.70|-1.00|| 1|O3G | 4|h_acc | N |LYS | | 16 |h_don |-4.70|-0.00|| 1|O2G | 3|h_acc | N |SER | | 17 |h_don |-4.70|-0.00|+---+----+----+-------------+----+----+-----+-----+-------------+-----+-----+
Christian Lemmen @ ACS, August 23rd 2004 17 © B
ioS
olve
IT G
mbH
the developers of FlexX
DDB: Virtual Screening Browser
FlexX Score∆Gbind = ∆GmatchFmatch + ∆GlipoFlipo + ∆GambigFambig + ∆GclashFclash + ∆Grotnrot
ScreenScore∆Gbind = Fmatch + 0.07(Flipo + Fambig) + 0.3FPLP + 1.6nrot
Present
[10] Stahl et al. JMC (2001)44, 1035-1042
Christian Lemmen @ ACS, August 23rd 2004 18 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Color Coded 2D Drawings
o
o
o
o
o
N
N
N
H
Christian Lemmen @ ACS, August 23rd 2004 19 © B
ioS
olve
IT G
mbH
the developers of FlexX
PresentDDB: Visualization of Interactions
Christian Lemmen @ ACS, August 23rd 2004 20 © B
ioS
olve
IT G
mbH
the developers of FlexX
FlexX Major Release 2.0 – What’s New ?Present
Up to 30-40% speedup on the PC due to performance tuning
Completely reworked and improved chemistry (static data)
Compatibility of major modules (-Pharm, -E, -C)
Added value in FlexX-Pharm (novel features)
PYTHON interface (rapid prototyping)
SMARTS support (define, transform, filter ...)
Support all big file formats (MOL2, SLN, cSLN, SDF, SMILES, PDB)
SAStab (made accessible), planar Amines (switch enabled)
TABcompletion, revised manual, improved error handling, ...
Windows version (read dos and unix files alike)
...
β available Sept/Oct
Christian Lemmen @ ACS, August 23rd 2004 21 © B
ioS
olve
IT G
mbH
the developers of FlexX
PlannedSMARTS in FlexX: What we can do
OH
O
NH2
O
ONH2
OH
O
NH
O-0.5
O-0.5
NH2
N
OH
O
NH2OH
O
OHNH2
O
O
NH2
+
C(=O)O >> C(-[OH]).O
*C(=O)O >> *.C(-[OH])O
NCCCC >> N1CCCC1
NCCC >> N=CC=C
C(=O)O >> C(:[O-0.5H]):[O-0.5]
C(=O)O >> C(=O)[O-]
C(=O)O >> C(=O)OCC
protonation
formal charges
bond types
ring closure
split
reduction
addition
Christian Lemmen @ ACS, August 23rd 2004 22 © B
ioS
olve
IT G
mbH
the developers of FlexX
Vision: Automatic Generation of AnalogesPlanned
Example: β-phenylethylamine family, derived by simple rules
NH2
OH NH
CH3
Ephedrin
OH NH2
OH
Octopamin
O
MeO
NH2OH
Metoprolol
O
NH2
O
NHCH3
CH3
OH
Atenolol
NH
OH
OH
OH
CH3
OH
Fenoterol
NH
OH
OH
OH
CH3
CH3CH3
Terbutalin
NH
OH
CH3
CH3CH3
OH
OH Salbutamol
NH
OH
CH3
CH3CH3
NH2
Cl
Cl Clenbuterol
NH2
OHOH
Dopamin
Christian Lemmen @ ACS, August 23rd 2004 23 © B
ioS
olve
IT G
mbH
the developers of FlexX
FlexX-Scan (More Rapid Virtual Screening)Planned
Spheres
Performance-tuned interaction model
Performance-tuned parametersfor base placement and complex buildup
6.95 sec/cpd on Linux (single Xeon 2.8 GHz CPU)
[12] Schellhammer et al. Proteins (2004), in print (available on-line)
© Z
BH
Christian Lemmen @ ACS, August 23rd 2004 24 © B
ioS
olve
IT G
mbH
the developers of FlexX
PlannedAn Example: Phosopholipase A2
Crystal complex with (R) 2-dodecanoyl-amino-1-hexanol-phosphoglycol
© Z
BH
Christian Lemmen @ ACS, August 23rd 2004 25 © B
ioS
olve
IT G
mbH
the developers of FlexX
PlannedFlexX-Scan Experiment
Screening data set from Didier Rognan*10 known Thymidine Kinase inhibitors990 randomly chosen drug-like compounds
Protein structure: automatically loaded from PDB (1kim) no manual preparation
FlexX-Scan 12 30 14 70 10 100
[*] Kellenberger et al. Comparative Evaluation of Eight Docking Tools for Docking andVirtual Screening Accuracy, Proteins (2004)57:225-242
Table 1*
© Z
BH
aver
age
run
tim
e
466718
234137118135108
22
Christian Lemmen @ ACS, August 23rd 2004 26 © B
ioS
olve
IT G
mbH
the developers of FlexX
ThanxX
Frank Schneider, Frank Sonnenburg, Gordon Müller, Holger Claußen,Ingo Dramburg, Marcus Gastreich, Markus Lilienthal, Sally Hindle, Sabine Trochim, Volker Apelt + a number of studentsMartin Stahl, Didier RognanMatthias Rareyand his group @ the University of HamburgIngo Schellhammer
& all our collaborators
and of courseyou for your attention
GRAFFINITYPharmaceutical Design GmbH
BoehringerIngelheim