A Collaborative Hit-to-Lead Investigation Leveraging Medicinal Chemistry Expertise with High Throughput Library Design, Synthesis and Purification Capabilities

Abstract

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.

Design and Diversity Analysis of Chemical Libraries in Drug Discovery

“…This discipline includes the management of biochemical or biological information from experimental data [104] and spectral data [105]. On the other hand, chemoinformatics is a fundamental tool in biochemical science research and biomedical areas related to biological systems, metabolomics, proteomics, and chemogenomics applied to drug discovery and development [106][107][108] 4.2. Bioinformatics Bioinformatics involves using computational analysis of biological data, which is relevant in pharmacological, biological, and biomedical studies [109].…”

Introduction to Cheminformatics

“…Until recently cheminformatics was a relatively obscure discipline with a comparatively small academic or industrial presence. However, with the advent of high throughput drug screening and the need for million-compound chemical libraries, cheminformatics is now playing a key role in many aspects of drug discovery and drug development. Cheminformatics is also playing a vital role in emerging fields such as chemical genomics (Yang et al, 2006), systems biology (Schnackenberg and Beger, 2006), and metabolomics (Schlotterbeck et al, 2006;Wishart et al, 2006). Indeed, as shall be seen shortly, cheminformatics has much to offer to the fields of molecular biology, biochemistry, and bioinformatics.…”