Fragment based drug discovery in teams of … · Fragment based drug discovery in teams of medicinal and computational chemists Carsten Detering ©

Fragment based drug discovery in teams of

medicinal and computational chemists

Carsten Detering

Mar 31 2011 © 2011 BioSolve IT GmbH 2 BioSolveIT @ Spring ACS Meeting, Anaheim, CA

BioSolveIT – Quick Facts

Founded in 2001

by the developers of FlexX

~20 people

Core expertise:

docking, screening, FBLD, GUIs

Offers collaborative custom development

licenses and contract maintenance

training and consulting services

Strong scientific backbone: Thomas Lengauer

Matthias Rarey

Gerhard Klebe

Hugo Kubinyi

Chris Lipinski


The LeadIT/ReCore idea

!

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Mar 31 2011 © 2011 BioSolve IT GmbH

Early Stage Teamformation

4 BioSolveIT @ Spring ACS Meeting, Anaheim, CA

Com

pChem

MedChem

Team


Link, Merge, Grow Fragments

ReCore in LeadIT


Case Study: Merging Fragments


Fragment Merging

The idea: Connect multiple known fragment binders where they overlap.

P. Hajduk: “Fragment-Based Drug Design at Abbott“

(Talk at the FBLD'2008, San Diego) and many, many others nowadays.


A Tough Merging Example

Thymidylate Synthase Inhibition à la Sunesis (Erlanson et al., PNAS 2000 97 9367)

N

SO

O

CO2-

PDB: 1F4E

Ki: 1.1mM

NH

N NH

N

N

O

NH

-O2C

-O2C

O

NH2

mTHF

Km: 14mM

“…tosyl group is in roughly the same

position and orientation as the benzamide

moiety of methylenetetrahydrofolate…”

N

SO

O

CO2-

NH

O

COO-

-O2C

24mM,

further opt‟d to 330nM



Thymidylate Synthase Inhibition à la Sunesis (Erlanson et al., PNAS 2000 97 9367)

N

SO

O

CO2-

NH

N NH

N

N

O

NH

-O2C

-O2C

O

NH2

N

SO

O

CO2-

NH

O

COO-

-O2C

Published Result

N

SO

O

CO2-

NH

COO-

-O2C

ReCore Rank 8

after 1sec.

To ensure the result accommodates in the pocket

the input ligand envelope shapes were used.




Case Study : Merging Fragments


A Fragment Merging Exercise

Adenosine Deaminase: Erlanson, D.A. et al., . J. Med. Chem. 2004, 47, 3463 ff.



Adenosine Deaminase: Erlanson, D.A. et al., . J. Med. Chem. 2004, 47, 3463 ff.

2e1w 1ndv




Case study: Growing a Fragment


Growing into a p-p Interaction Pattern

Bcl-2 protein example from Abbott (Oltersdorf et al, Nature 435 (2005) 677).

Let us try to get the p-stacking right as in the original finding in ABT-737

p

p

2 vectors are needed for the Query:

a) Exit Vector

b) p-interaction „Pharm. Feature‟

Site 1 Site 2

N N

Cl

O

NH

SO2

NO2

NH N

S

N N

Cl

O

NH

SO2

NO2



Here it is in 3D:

„helping‟

Ph inserted



The Result in 2D:

ABT-737

ReCore Solution No.11:

N N

Cl

O

NH

SO2

NO2

NH N

S

N N

Cl

O

NH

SO2

NO2

NH N

S

OO



Solution No. 11 in comparison to ABT-737 (green):

Almost identical positions obtained!


Software for Medicinal Chemists


User Interaction

Handle Chemistry 1

2

3

Grow With Requirements

Make MedChems happy!


Roche 2007: Scaffold Hopping Using Vectors

define “Exit Vectors” search 3D fragment library

=> ReCore. Software development by Maass, Rarey (ZBH, Hamburg) and Roche

Maaß, Schulz-Gasch, Stahl Rarey, J. Chem. Inf. Mod., 47, 390-399 (2007)

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Index Generation


Index


Index

Standard Workflow

+

Input mol2

O

NH

O

NH

S

NH2

Reasonable

Fragments

Rules Index

3 2 1


ReCore: Indexed Searching


ReCore: Indexed Searching

The Index needs a pre-generated “descriptor”:

ReCore: Vector relationships Telephone book: alphabet


Google-like Searching

The better the geometric fit, the better the rank

LeeeeeeaaaaaaaaadIT

I feel lucky


ReCore: Results Delivery

By design the best fitting replacements are found first

The ranking is according to deviation from perfect vector overlap

Rank 1

Rank 2

Rank 3

Rank 4 ReCore Query


A ReCore Specialty: “3D Shredding”

“partial enumeration“

trivial fragmentation q1

q1

q2

q2


Bring in chemists in every step

Fragment creation:

Retrosynthetic shredding rules = sensible fragments

Query defintion:

Cut where chemists can synthesize

Results

Forbid unwanted

bond formation


N

O O

A

'C

B

Bring in low energy conformations

1. Torsions within the fragment (typically from experiment)

N

O S

A

'C

B

torsions controllable by user,

connections can even be forbidden

„observed‟ prior to indexing

۷ ۷ ۷ Torsions fixed Torsions fixed Torsions fixed

2. Torsions upon

new single bonds

formation: Link

Constraints

3 2 1


Intuitive Interface


Wrap-up LeadIT/ReCore in teams

Technology

Key applications

Core replacement

Fragment linking & merging

Fragment growing

Docking (pose checking)

Binding affinity assessment

Key advantages

Low energy conformations (-> bioactivity)

Pharmacophores (-> target specificity)

Grows with requirements (-> IP)

Interactive search (-> TEAM building)

Use fragments (-> chemical universe)

Index created by user

3

2

1



www.biosolveit.com

[email protected]


Wrap-up LeadIT/ReCore in teams

Technology

Key applications

Core replacement

Fragment linking & merging

Fragment growing

Docking (pose checking)

Binding affinity assessment

Key advantages

Low energy conformations (-> bioactivity)

Pharmacophores (-> target specificity)

Grows with requirements (-> IP)

Interactive search (-> TEAM building)

Use fragments (-> chemical universe)

Index created by user

3

2

1

Documents

Fragment based drug discovery in teams of … · Fragment based drug discovery in teams of medicinal and computational chemists Carsten Detering ©