Computational method for the systematic alignment of analogue series with structure-activity relationship transfer...

Lead optimization focuses on the generation of analogue series (ASs) with sustainable structure-activity relationship (SAR) progression. If roadblocks are encountered during multi-property optimization, it is often desirable to replace an AS with another containing a different core structure but having similar SAR characteristics for a given target. This process represents target-based SAR transfer. A previously unexplored question is to what extent AS-based SAR transfer events might also occur across different targets. To address this question, we have developed and applied a new computational approach to systematically search for ASs with SAR transfer potential and align qualifying series in a chemically intuitive way. The methodology relies on fragment similarity scoring in combination with dynamic programming. Our large-scale analysis has revealed that SAR transfer events across different targets are more frequently observed than one might expect, providing many opportunities for the design of new SAR transfer analogues for evolving series.