A chemistry friendly system integrating drug design tools and a consistent visual interface Xin Zhang, Christian Baber

Transcription

1 Cubist Pharmaceuticals The Shape of Cures to Come A chemistry friendly system integrating drug design tools and a consistent visual interface Xin Zhang, Christian Baber

2 Outline Introduction to drug metabolism Introduction to Cubist Discovery Informatics group The DT workbench Case study

3 Outline Introduction to drug metabolism Introduction to Cubist Discovery Informatics group The DT workbench Case study

4 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

5 Ticrynafen A diuretic drug to treat hypertension Withdrawn in 1980 only a few months after launched Several hundred cases of liver injury reported, 25 deaths Covalent binding of metabolites to human liver microsomes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) Reactive Thiophene epoxide Reactive Thiophene sulfoxide

6 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,

7 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

8 Outline Introduction to drug metabolism Introduction to Cubist Discovery Informatics group The DT workbench Case study

9 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

10 Outline Introduction to drug metabolism Introduction to Cubist Discovery Informatics group The DT workbench Case study

11 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

12 DT workbench main user interface ChemAxon components in Pipeline Pilot used to calculate some properties Tree menu organizes tools/models Integrated Marvin Sketch Applet, no end user software installation - especially important for end users without admin privileges Consistent layout Customizable input form depends on run parameters Templates based system allow reuse of existing forms Option to retrieve result by for big jobs

13 System Architecture - the design for DT workbench DT Workbench MarvinSketch Applet MarvinView Applet 13

14 System Architecture - the design for DT workbench MarvinSketch Applet MarvinView 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

15 Outline Introduction to drug metabolism Introduction to Cubist Discovery Informatics group The DT workbench Case study

16 Case study Identify potential liability of Ticrynafen by predicting its SOM Lead hopping searching new ideas Evaluating the new structure overlay with Ticrynafen

17 Start with Ticrynafen s structure Cytochrome P450 isozyme model to use Integrated with Marvin Sketch for structure drawing

18 Running prediction on the server Information about the Job: task name, and status Change your mind after job submitted? You can still get the results by

19 Predicted results identified site of metabolism Predicted result is from scripts in sdf file format no interface Thiophene is the main site of metabolism Label the SOM atoms Highlight the primary SOM Part of MarvinView, automatically display relevant properties based on model run Customized MarvinView to visualize predicted results - Critical information is directly displayed on the structure - Thanks to Marvin API, difficult to do this with ChemDraw

20 Predicted results identified site of metabolism SOM_viewer.jsp Simple coding with Marvin API Self-taught by reading ChemAxon Documents

21 Case studies Identify potential liability of Ticrynafen by predicting its SOM Lead hopping searching new ideas Evaluating the new structure overlay with Ticrynafen

22 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

23 Thiophene replacement Lead hopping Find replacement with similar biological activity Similar Template

24 Thiophene replacement Lead hopping 2D structure viewer customized with Marvin view

25 2D Structure View Multiple compounds Switch view types Display by pages Customized interface Thiophene replacements 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. Toggle to display/hide properties

26 Case studies - continue Identify potential liability of Ticrynafen by predicting its SOM Lead hopping searching new ideas Evaluating the new structure overlay with Ticrynafen

27 Evaluate the new structure slight modification of interface - same components

28 3D structure overlay 2D structure viewer not relevant here 3D structure viewer jmol Needs improvement MarvinSpace evaluated, but not adopted due to slow loading of pdb files in our server environment

29 Drug metabolism prediction and drug design O Ticrynafen (withdrawn in 1980) O OH O Cl Cl S Secondary Tertiary C Primary Predicted primary SOM bioisostere Edecrin by Merck (approved in 1999) non-standard bioisostere

30 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

31 Acknowledgements Jie Wu Northeastern Cooperative Student Dominic Ryan Senior Director, DT Cubist Pharmaceuticals Curt M. Breneman Professor and Department Head, Department of Chemistry and Chemical Biology Open-source 3D structure viewer THANKS!