Molecular Diversity Management Strategies for Building and Enhancement of Diverse and Focused Lead Discovery Compound Screening Collections

Abstract

This publication describes processes for the selection of chemical compounds for the building of a high-throughput screening (HTS) collection for drug discovery, using the currently implemented process in the Discovery Technologies Unit of the Novartis Institute for Biomedical Research, Basel Switzerland as reference. More generally, the currently existing compound acquisition models and practices are discussed. Our informatics, chemistry and biology-driven compound selection consists of two steps: 1) The individual compounds are filtered and grouped into three priority classes on the basis of their individual structural properties. Substructure filters are used to eliminate or penalize compounds based on unwanted structural properties. The similarity of the structures to reference ligands of the main proven druggable target families is computed, and drug-similar compounds are prioritized for the following diversity analysis. 2) The compounds are compared to the archive compounds and a diversity analysis is performed. This is done separately for the prioritized, regular and penalized compounds with increasingly stringent dissimilarity criterion. The process includes collecting vendor catalogues and monitoring the availability of samples together with the selection and purchase decision points. The development of a corporate vendor catalogue database is described. In addition to the selection methods on a per single molecule basis, selection criteria for scaffold and combinatorial chemistry projects in collaboration with compound vendors are discussed.

A Chemoinformatics Analysis of Hit Lists Obtained from High-Throughput Affinity-Selection Screening

“…There are many published methods that are intended to assist in the design of molecular libraries for screening campaigns by suggesting a subset of molecules that should be considered for testing. [12][13][14][15][16] Typically, it is accepted that a designed diverse subset of molecules is desirable because the intention of such a design is to cover the chemistry space represented in the entire data set. As with the determination of molecular scaffolds, however, there is currently no single rigorous definition of molecular diversity that is acceptable to all practitioners in the field of chemoinformatics-essentially a trade-off between covering the extremities of the space and representing the distribution of data points within that space.…”

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

“…The design criteria for lead generation libraries, where the potential virtual space to be covered by the array is quite large, have traditionally been driven by the diversity of the potential products to be prepared. More recently, considerations regarding the drug-likeness of the compounds to be prepared have been added to the design criteria for lead generation libraries [8]. The ArQule technology platform includes a suite of design software that performs these evaluations and assists the chemist in selecting the appropriate reagents to prepare products having the desired parameter profile.…”

Key Aspects of the Novartis Compound Collection Enhancement Project for the Compilation of a Comprehensive Chemogenomics Drug Discovery Screening Collection

“…(1)) [12]. The structural diversity is of particular importance; not only exact duplication needs to be avoided, but a general diversity in terms of chemical classes, lead and drug-likeness needs to achieved [13][14][15].…”

“…The incremental diversity selections are done with decreasing similarity thresholds and compound densities. For further detail see reference [12]. ligands of proven druggable target families of interest is then computed, and the compounds similar to drugs and known actives are prioritized for the following diversity analysis.…”