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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22310%2F25%3A43932410" target="_blank" >RIV/60461373:22310/25:43932410 - isvavai.cz</a>

Result on the web

<a href="https://jcheminf.biomedcentral.com/articles/10.1186/s13321-024-00910-4#citeas" target="_blank" >https://jcheminf.biomedcentral.com/articles/10.1186/s13321-024-00910-4#citeas</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s13321-024-00910-4" target="_blank" >10.1186/s13321-024-00910-4</a>

Result language

angličtina

Original language name

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

Original language description

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. Scientific contribution Our core scientific contribution is the introduction of in-house de novo drug design, which enables the practical application of generative methods in small laboratories by utilizing a limited stock of available building blocks. Our fast-to-adapt workflow for in-house synthesizability scoring requires minimal computational retraining costs while supporting a high diversity of generated structures. We highlight the practicality of our approach through a comprehensive in-vitro case study that relies entirely on in-house resources, including in-silico generation, synthesis planning, and activity evaluation.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10200 - Computer and information sciences

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Cheminformatics

ISSN

1758-2946

e-ISSN

—

Volume of the periodical

17

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

16

Pages from-to

nestránkováno

UT code for WoS article

001455836700001

EID of the result in the Scopus database

2-s2.0-105001323842