Design and Crystallographic Screening of a Highly Sociable and Diverse Fragment Library Towards Novel Antituberculotic Drugs

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 chemical space around a fragment of interest without much effort. Here, this library was used for a crystallographic fragment screening on a mycobacterial thioredoxin reductase to identify new starting points for developing new anti-tuberculotic agents. Several hits have been identified in a preliminary analysis of the screening.