Generate what you can make: achieving in-house synthesizability with readily available resources in de novo drug design

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Alan Kai Hassen, Martin Šícho, Yorick J. van Aalst, Mirjam C. W. Huizenga, Darcy N. R. Reynolds, Sohvi Luukkonen, Andrius Bernatavicius, Djork-Arné Clevert, Antonius P. A. Janssen, Gerard J. P. van Westen, Mike Preuss

Published: 28 Mar 2025, Last Modified: 29 Jan 2026Journal of CheminformaticsEveryoneRevisionsCC BY-SA 4.0
Abstract: Computer-Aided Synthesis Planning (CASP) and CASP-based approximated synthesizability scores have rarely been used as generation objectives in Computer-Aided Drug Design despite facilitating the in-silico generation of synthesizable molecules. However, these synthesizability approaches are disconnected from the reality of small laboratory drug design, where building block resources are limited, thus making the notion of in-house synthesizability with already available resources highly desirable. In this work, we show a successful in-house de novo drug design workflow generating active and in-house synthesizable ligands of monoglyceride lipase (MGLL). First, we demonstrate the successful transfer of CASP from 17.4 million commercial building blocks to a small laboratory setting of roughly 6000 building blocks with only a decrease of –12% in CASP success when accepting two reaction-steps longer synthesis routes on average. Next, we present a rapidly retrainable in-house synthesizability score, successfully capturing our in-house synthesizability without relying on external building block resources. We show that including our in-house synthesizability score in a multi-objective de novo drug design workflow, alongside a simple QSAR model, provides thousands of potentially active and easily in-house synthesizable molecules. Finally, we experimentally evaluate the synthesis and biochemical activity of three de novo candidates using their CASP-suggested synthesis routes employing only in-house building blocks. We find one candidate with evident activity, suggesting potential new ligand ideas for MGLL inhibitors while showcasing the usefulness of our in-house synthesizability score for de novo drug design.