Accessing Ultralarge Chemical Spaces via a Sociable Fragment Library: Design and Crystallographic Screening

02 April 2025, Version 3
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Missing synthetic tractability is a common pitfall that is often impeding fragment-to-lead campaigns. Ideally, the follow-up fragment extension would be performed quickly and exhaustively, leading to novel hit or lead compounds in rapid succession without the need for tediously developing synthetic methodologies. However, no fragment library currently has this so-called “sociability” as its primary design principle. Herein, we describe the development of a 96-membered, highly diverse, and entirely sociable fragment library suitable for crystallographic screening. Hundreds to thousands of follow-up compounds modified at all growth vectors are available for each fragment from Enamine’s REAL Space. Additionally, tens to hundreds of thousands of larger and more complex leadlike molecules are accessible per library member, further expanded by scaffold-modified, alternative fragments. This allows for rapid exploration of the ultralarge chemical spaces for a specific target using fragment screening. As a proof-of-concept, the designed sociable library was used for crystallographic fragment screenings on a mycobacterial thioredoxin reductase and the NS2B-NS3 protease of the Zika virus. The high sociability allowed us to follow up experimentally on two promising fragments rapidly by selecting and testing 120 fragment extensions out of Enamine’s REAL Space.

Keywords

Fragment-based drug discovery
Fragment library
Sociable Fragments
Medicinal Chemistry
Drug Discovery

Supplementary materials

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Description
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Supplemental Information
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Further information on the sociable fragment library and collected data.
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