What else can you do with the Markush cartridge? Tracking chemical series for project teams

Gregory Landrum Ph.D., Anna Pelliccioli Ph.D. NIBR Informatics

Novartis Institutes for BioMedical Research

Basel

ChemAxon UGM 2014 Cambridge, MA

The Problem

§  Medicinal chemists frequently use the idea of the “Series” as an organizing principle.

§  A compound belongs to a Series if its structure contains a particular substructure or scaffold

§  Scaffold definitions are ‘in the Chemist’s head’ or in some local files §  Learnings/decisions from med chem projects are typically associated

with the individual series. •  “We were unable to achieve selectivity with series A” •  “Series B has metabolic liabilities” •  “We decided to start lead-optimization activities with series C”

§  Series-level knowledge stays with scientists or, at best, in slide decks

The Compound Series and Favorites Project (CSF)

§  Provide scientists with a shared space to store scaffold definitions and most significant compounds (Favorites).

§  Structures should be searchable within the new application §  Scientists should be able to annotate structures and scaffolds to

capture their learnings §  Everything should be accessible from other applications (like Spotfire)

via web services

An aside

§  All structures and data in this presentation are taken from public data sources: •  Neil R. Curtis, Janusz J. Kulagowski, Paul D. Leeson, Mark P. Ridgill, Frances Emms, Stephen B.

Freedman, Shil Patel, Smita Patel, 1999, 'Synthesis and sar of 2- and 3-substituted 7-azaindoles as potential dopamine D4 ligands', Bioorganic & Medicinal Chemistry Letters, vol. 9, no. 4, pp. 585-588

•  Thomas R. Belliotti, Wouter A. Brink, Suzanne R. Kesten, John R. Rubin, David J. Wustrow, Kim T. Zoski, Steven Z. Whetzel, Ann E. Corbin, Thomas A. Pugsley, Thomas G. Heffner, Lawrence D. Wise, 1998, 'Isoindolinone enantiomers having affinity for the dopamine D4 receptor', Bioorganic & Medicinal Chemistry Letters, vol. 8, no. 12, pp. 1499-1502

•  Christian Haubmann, Harald Hübner, Peter Gmeiner, 1999, 'Piperidinylpyrroles: Design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands', Bioorganic & Medicinal Chemistry Letters, vol. 9, no. 21, pp. 3143-3146

•  Hubert H. M. Van Tol, James R. Bunzow, Hong-Chang Guan, Roger K. Sunahara, Philip Seeman, Hyman B. Niznik, Olivier Civelli, 1991, 'Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine', Nature, vol. 350, no. 6319, pp. 610-614

•  Jalaj Arora, Michel Bordeleau, Laurence Dube, Keith Jarvie, Lucy Mazzocco, Jack Peragine, Ashok Tehim, Ian Egle, 2005, 'N-[(3S)-1-Benzylpyrrolidin-3-yl]-(2-thienyl)benzamides: Human dopamine D4 ligands with high affinity for the 5-HT2A receptor', Bioorganic & Medicinal Chemistry Letters, vol. 15, no. 23, pp. 5253-5256

§  Chemical structures exported from ChEMBL 19.

CSF – the system

§  Web-based front end: •  Bootstrap + JQuery •  ChemDraw •  Avalon toolkit for structure rendering •  Calls out to multiple NIBR services

§  CSF Service Layer: •  Java-based REST services •  RDKit for structure validation

§  Database:

• Oracle + JChem + Markush extensions

CSF – the home page

Project Overview

Three series

Compound

Scaffold

Series overview

Detail Page and Path

Detail Page and Path

reasoning

Detail Page and Path

source(s)

Adding sources

Detail Page and Path

tags

Tags

Detail Page and Path

links

Detail Page and Path

notes

Adding compound/scaffold

Markush features

Several Markush features can be used to define scaffolds Not all features are supported: depends on what the cartridge can store as a target and what our internal renderer can display

Supported Markush features

Checking for unsupported generic features

Search + Markush

Finds both compounds and scaffolds

Search + Markush - alternative

structure search + other criteria

Integration with other tools: Spotfire

Selecting scaffolds/compounds Lists populated from CSF’s service layer

Integration with other tools: Spotfire

Editing, renaming

Integration with other tools: Spotfire

Using the scaffolds

Acknowledgements §  Project team

•  Anna Pelliccioli •  Manuel Schwarze •  Recca Chatterjee •  Mikhail Rybalkin •  Roman Bolshev

§  Acceptance Team •  Natalie Dales •  Stefanie Flohr •  Greg Hollingworth •  Patrick Lee •  Wolfgang Miltz •  Ansgar Schuffenhauer

§  Advisory Team •  Mark Burfoot •  John Davies •  Jeremy Jenkins •  Greg Landrum •  Greg Paris •  Tim Smith

§  Others •  Nico Pulver •  Guido Koch •  Hans Widmer

§  ChemAxon •  Andras Volford