Design, Synthesis and Biological Screening of 3-D Fragments: York 3-D Fragment Library

The O’Brien group is exploring the construction of a novel 3-D fragment library for fragment-based drug discovery. Fragments are relatively simple, small organic molecules with molecular weight of 110-250 Da, clogP values in the range –1 to 3 and total polar surface area of ≤60 Å. However, current fragment libraries are populated with a high proportion of flat, heteroaromatic structures and this can limit the exploration of fragment-protein interactions. To address this, we are designing 3-D fragments that occupy regions of under-represented 3-D pharmaceutical space. The new 3-D fragments are then screened against protein targets of relevance to drug discovery, with interesting hits against two covid-19 proteins. The synthetic element of this project has benefitted from support from an industrial consortium of partners, including Astex, AstraZeneca, Lilly, Pfizer, Vernalis and Asahi Kasei.