eugm15: anna pelliccioli (novartis) what else can you do with the markush cartridge? tracking...

What else can you do with the Markush cartridge?

Tracking chemical series for project teams

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

NIBR Informatics

Novartis Institutes for BioMedical Research

Budapest, ChemAxon UGM 2015

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.

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

2 | Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only

Capturing the relationships among structures and series

Martin Stahl1,* and Sabine Baier, ChemMedChem, published online 2015

1) Typical full article covering SAR around a

lead; 2) Review article

covering the latest developments across

compound classes; 3) Case study

outlining the history of a single molecule

reaching clinical stages of development.

The terms “screening hit” and “candidate” are

placeholders for chemical

entry points of any kind (including compounds

from other projects) and

desired end points that may be defined in many

different ways

Series ASeries B

Series C


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



source(s)



links


eugm15: anna pelliccioli (novartis) what else can you do with the markush cartridge? tracking...

Software

compound series

tracking chemical series

series b series c

individual series

series martin stahl1

different ways series

project teams anna pelliccioli

chemaxon ugm