Diversity Quantification of Chemical Libraries

Colliandre L, Le Guilloux V, Bourg S, Morin-Allory L. "J Chem Inf Model. 2011 Dec"

High Throughput Screening (HTS) can be a standard technique widely useful to find hit compounds within drug discovery projects. The high costs associated with such experiments have highlighted the necessity to carefully design screening libraries to avoid wasting resources. Molecular diversity is an established concept that's used to this end for many years.

A new approach to help quantify the molecular diversity of screening libraries is usually presented nowdays. The approach is dependent on the Delimited Reference Chemical Subspace (DRCS) strategy, a new method that can be used to delimit the densest subspace spanned by a reference library in a lower life expectancy 2D continuous space. An overall of twenty-two diversity indices have been implemented or adapted to the current methodology, which is used here to take out outliers and obtain another cell-based partition of that subspace.

The behavior these indices was assessed and compared in various extreme situations, and with respect to a set of theoretical rules that a diversity function should satisfy when libraries of different sizes have to be compared. Some gold standard indices are found inappropriate ordinary context, while none of the tested indices behave perfectly in all cases. Five DRCS-based indices accounting for different aspects of diversity were lastly selected, and a simple framework is proposed to use them effectively.

Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of significant chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' capacity and selectivity profiles.

However, high attrition of targeted agents in clinical development claim that combinations of targeted agents is going to be most effective in treating solid tumors in the event the biological networks that allow cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and advancement strategies are suboptimal for any rational design and advancement of novel drug combinations.

In this article, we highlight several emerging technologies supporting some sort of less reductionist, more agile, drug-discovery and development approach for any rational design, validation, prioritization together with clinical development of innovative drug combinations.