Systematic Identification of Matching Molecular Series and Mapping of Screening Hits.

Abstract

Matching molecular series (MMS) have originally been introduced as an extension of the matched molecular pair (MMP) concept to facilitate the design of substructure-based structure-activity relationship (SAR) networks. An MMP is defined as a pair of compounds that only differ by a structural change at a single site. In addition, an MMS is defined as an MMP-based series of compounds that have a conserved structural core and are distinguished by modifications at a single site. Systematic generation of MMS from specifically active compounds generalizes the search for series of structural analogs. Potency-ordered MMS provide series associated with SAR information. We have systematically extracted MMS from publicly available compounds with well-defined activity measurements and generated a large database with approx. 40 000 single- and 13 600 multi-target series, which provide a rich source of SAR information. As an application, we introduce MMP-based mapping of screening hits to MMS to search for initial SAR information and determine all SAR environments available for such hits. The MMS database is made freely available to the scientific community.