USUGM 2014 - Xin Zhang (Cubist): A chemistry friendly system integrating drug design tools

The Shape of Cures to Come™

Cubist Pharmaceuticals

A chemistry friendly system integrating drug design tools and a consistent visual interface

Xin Zhang, Christian Baber

Outline

Introduction to drug metabolism

Introduction to Cubist Discovery Informatics group

The DT workbench

Case study

Outline



The DT workbench

Case study

Drug metabolism

Convert drugs into other products (metabolites) within the body

Controls the duration and intensity of the action of many drugs

Over 50% of drug development failures can be associated with metabolic effects

In general metabolites are more easily excreted than the original drug

Secondary pharmacological implications

– Normally pharmacologically inert

– Sometime they are pharmacologically active.

• similar activity to the drug

• or a different activity

• or be toxic

Ticrynafen

A diuretic drug to treat hypertension

Withdrawn in 1980 only a few months after launched

Several hundred cases of liver injury reported, 25 deaths

Covalent binding of metabolites to human liver microsomes reported

Cytochrome P450 isozyme 2C9(CYP2C9)

Thiophene epoxide Thiophene sulfoxide

Reactive

Reactive

RS Predictor – A SOM Prediction Model

Models predict site of metabolism (SOM) for given structures

A QSAR model developed by Prof. Breneman’s group in Rensselaer Polytechnic Institute *

Isozyme specific, 9 available

– Cytochrome P450 isozymes 1A2, 2A6, 2B6, 2C19, 2C8, 2C9, 2D6, 2E1, and 3A4

Academic scientific project with technical limitations

– Command line only, no graphic interface

– Structure files input/output – bad for chemists

– Single user only, not capable of running predictions simultaneously

– Dependencies on MOE and MatLab

* Jed Zaretzki, Patrik Rydberg, Charles Bergeron, Kristin P. Bennett, Lars Olsen, and Curt M. Breneman, J. Chem. Inf. Model. 2012, 52, 1637−1659

RS Predictor at Cubist

Modify the run scripts to manage

– MOE floating licenses

– Matlab license

– Multiple users, not overwrite results

– Simultaneous runs

– Output result folders

Allow input structure from a drawing package

– MarvinSketch

Visualize the prediction results

– MarvinView (customized to display atom label and highlight)

More details on integration later

Outline



The DT workbench

Case study

Discovery Informatics

Not a software development team– involved in bringing in new technologies

Part of Discovery Technologies (DT) - a hybrid group consisting of– chemo- and bio- informatics– molecular modeling– compound management– High Throughput Screening – NMR / Biophysics

Every cheminformatician supports at least one research project– Driving project SAR– Generating ideas using computational technologies– Ensuring the availability & integration of data– Chemical and biological data management

Outline



The DT workbench

Case study

DT Workbench - background

Used to publish models for access by chemists

– User friendly, web based instead of script based

– Many expert tools are command line only

– Created, maintained, and expanded by DT scientists, not IT

Feedback has been very positive

– Started as a prototype in 2008

– Lead to substantial update in 2012

• ChemOffice replaced by ChemAxon Marvin

• Increased usage since updates

Low maintainence: 3tier web-based system

– Thin client that utilize existing servers and storage disks

– No installation at the user end

Templates: Consistent but customizable front end

– Apps have different fields depends on inputs parameters

– Templates allow reuse of existing forms

– Common components reduces training requirement

Scalability: Re-designed system architecture to incorporate new technologies, such as Marvin suite for both input and visualization

DT workbench – main user interface

Tree menu organizes tools/models

Consistent layout

Option to retrieve result by email – for big jobs

• Customizable input form depends on run parameters

• Templates based system allow reuse of existing forms

Integrated Marvin Sketch Applet, no end user software installation- especially important for end users without admin privileges

ChemAxon components in Pipeline Pilot used to calculate some properties

System Architecture- the design for DT workbench

13

DT Workbench

MarvinSketch AppletMarvinView Applet

System Architecture- the design for DT workbench

MarvinSketch AppletMarvinView Applet

• Communicate back to Tomcat server to send the structure data• Compatible with Cubist supported browser and platform• Better fit within W3C standard HTML than ActiveX (ChemDraw)• Communication between Javascript and Java - enable interactive view

Outline



The DT workbench

Case study

Case study

Identify potential liability of Ticrynafen by predicting its SOM

Lead hopping – searching new ideas

Evaluating the new structure – overlay with Ticrynafen

Start with Ticrynafen’s structure

Integrated with Marvin Sketch for structure drawing

Cytochrome P450 isozymemodel to use

Running prediction on the server

Change your mind after job submitted? You can still get the results by email

Information about the Job: task name, and status

Predicted results – identified site of metabolism

Customized MarvinView to visualize predicted results- Critical information is directly displayed on

the structure- Thanks to Marvin API, difficult to do this

with ChemDraw

Predicted result is from scripts in sdf file format – no interface

Thiophene is the main site of

metabolism

Part of MarvinView, automatically display relevant properties based on model run

Highlight the primary SOM

Label the SOM atoms

Predicted results – identified site of metabolism

SOM_viewer.jsp

• Simple coding with Marvin API• Self-taught by reading ChemAxon Documents

Case studies




Thiophene replacement – Lead hopping

Take the output of current run into the next job

Thiophene was identified as primary site

of metabolism so we want to replace it


Find replacement with similar biological activity

Similar Template


2D structure viewer – customized with Marvin view

2D Structure View – Multiple compounds

Customized interface

Integrated with Knime– Knime pre-processes the SDF file

• Standardize structures / tidy file

• Chunk file for multiple page display

MarvinView API used

– Table layout

– Structure display parameters

– Event listener, etc.

Switch view types Display by pages

Toggle to display/hide properties

Thiophenereplacements

Case studies - continue




Evaluate the new structure

slight modification of interface- same components

3D structure overlay

3D structure viewer – jmolNeeds improvement

MarvinSpace evaluated, but not adopted due to slow loading of pdbfiles in our server environment

2D structure viewer – not relevant here

Drug metabolism prediction and drug design

Ticrynafen(withdrawn in 1980)

TertiaryCPrimary

O

O

OH

O

SSecondary

Cl

Cl

Predicted primary SOM

non-standard bioisostere

Edecrin by Merck(approved in 1999)

bioisostere

Summary

Metabolism Plays Central Role in Drug Discovery– Computational models can help

Integrated Web-based Applications Reduce Learning Curves– Standard components and templates

Technologies such as Marvin enable Quick, Inexpensive, Simple Solutions– 6 month develop by a co/op student from North Eastern university

– Low maintenance - requires no additional IT support

Marvin Sketch Applet is Consistent but Flexible– Easily implemented in web pages - no end user installation

– Wide range of file formats allows common interface for different Workbench models

Marvin View/Structure Renderer is Adaptable to Various Needs – Highlight specified atoms & bonds

– Add labeling and captioning text

– Interactive Spreadsheet and Grid formats available

Don’t be Limited by the Out of Box Interfaces– Marvin customization is easy

Acknowledgements

Curt M. Breneman Professor and Department Head, Department of Chemistry and Chemical Biology

Jie WuNortheastern Cooperative Student

Dominic RyanSenior Director, DTCubist Pharmaceuticals

Open-source 3D structure viewer

THANKS!

Software

USUGM 2014 - Xin Zhang (Cubist): A chemistry friendly system integrating drug design tools