J Chem Inf Model - Visual characterization and diversity quantification of chemical libraries: 2. Analysis and selection of size-independent, subspace-specific diversity indices.

Tópicos

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Resumo

High Throughput Screening (HTS) is a standard technique widely used to find hit compounds in drug discovery projects. The high costs associated with such experiments have highlighted the need to carefully design screening libraries in order to avoid wasting resources. Molecular diversity is an established concept that has been used to this end for many years. In this article, a new approach to quantify the molecular diversity of screening libraries is presented. The approach is based on the Delimited Reference Chemical Subspace (DRCS) methodology, a new method that can be used to delimit the densest subspace spanned by a reference library in a reduced 2D continuous space. A total of 22 diversity indices were implemented or adapted to this methodology, which is used here to remove outliers and obtain a relevant cell-based partition of the subspace. The behavior of 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 in such a context, while none of the tested indices behave perfectly in all cases. Five DRCS-based indices accounting for different aspects of diversity were finally selected, and a simple framework is proposed to use them effectively. Various libraries have been profiled with respect to more specific subspaces, which further illustrate the interest of the method.

Resumo Limpo

high throughput screen hts standard techniqu wide use find hit compound drug discoveri project high cost associ experi highlight need care design screen librari order avoid wast resourc molecular divers establish concept use end mani year articl new approach quantifi molecular divers screen librari present approach base delimit refer chemic subspac drcs methodolog new method can use delimit densest subspac span refer librari reduc d continu space total divers indic implement adapt methodolog use remov outlier obtain relev cellbas partit subspac behavior indic assess compar various extrem situat respect set theoret rule divers function satisfi librari differ size compar gold standard indic found inappropri context none test indic behav perfect case five drcsbase indic account differ aspect divers final select simpl framework propos use effect various librari profil respect specif subspac illustr interest method

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