posted on 2024-02-13, 09:04authored byFrançois Sindt, Anthony Seyller, Merveille Eguida, Didier Rognan
Ultralarge chemical
spaces describing several billion compounds
are revolutionizing hit identification in early drug discovery. Because
of their size, such chemical spaces cannot be fully enumerated and
require ad-hoc computational tools to navigate them and pick potentially
interesting hits. We here propose a structure-based approach to ultralarge
chemical space screening in which commercial chemical reagents are
first docked to the target of interest and then directly connected
according to organic chemistry and topological rules, to enumerate
drug-like compounds under three-dimensional constraints of the target.
When applied to bespoke chemical spaces of different sizes and chemical
complexity targeting two receptors of pharmaceutical interest (estrogen
β receptor, dopamine D3 receptor), the computational method
was able to quickly enumerate hits that were either known ligands
(or very close analogs) of targeted receptors as well as chemically
novel candidates that could be experimentally confirmed by in vitro binding assays. The proposed approach is generic,
can be applied to any docking algorithm, and requires few computational
resources to prioritize easily synthesizable hits from billion-sized
chemical spaces.