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BioSolveITBiology Problems Solved using Information Technology

FlexXpast, present, and planned

technological advancementsChristian Lemmen

Christian Lemmen @ ACS, August 23rd 2004 2 © B

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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

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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

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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

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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

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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

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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

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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

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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

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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

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PresentDDB: Our Database Connection

how we usually describe ‘the problem’

©C

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Christian Lemmen @ ACS, August 23rd 2004 12 © B

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PresentDDB: Our Database Connection

how we usually describe ‘the problem’

... we propose to get a little more organized

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Christian Lemmen @ ACS, August 23rd 2004 13 © B

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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

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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

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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

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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

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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

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PresentDDB: Color Coded 2D Drawings

o

o

o

o

o

N

N

N

H

Christian Lemmen @ ACS, August 23rd 2004 19 © B

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PresentDDB: Visualization of Interactions

Christian Lemmen @ ACS, August 23rd 2004 20 © B

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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

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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

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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

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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)

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PlannedAn Example: Phosopholipase A2

Crystal complex with (R) 2-dodecanoyl-amino-1-hexanol-phosphoglycol

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Christian Lemmen @ ACS, August 23rd 2004 25 © B

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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*

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aver

age

run

tim

e

466718

234137118135108

22

Christian Lemmen @ ACS, August 23rd 2004 26 © B

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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