Customizable Generation of Synthetically Accessible, Local Chemical Subspaces

Screening
large libraries of chemicals has been an efficient strategy
to discover bioactive compounds; however a portion of the potential
for success is limited to the available libraries. Synergizing combinatorial
and computational chemistries has emerged as a time-efficient strategy
to explore the chemical space more widely. Ideally, streamlining the
evaluation process for larger, feasible chemical libraries would become
commonplace. Thus, combinatorial tools and, for example, docking methods
would be integrated to identify novel bioactive entities. The idea
is simple in nature, but much more complex in practice; combinatorial
chemistry is more than the coupling of chemicals into products: synthetic
feasibility includes chemoselectivity, stereoselectivity, protecting
group chemistry, and chemical availability which must all be considered
for combinatorial library design. In addition, intuitive interfaces
and simple user manipulation is key for optimal use of such tools
by organic chemistscrucial for the integration of such software
in medicinal chemistry laboratories. We present herein Finders and React2Dintegrated into the Virtual Chemist platform, a modular software suite. This approach
enhances virtual combinatorial chemistry by identifying available
chemicals compatible with a user-defined chemical transformation and
by carrying out the reaction leading to libraries of realistic, synthetically
accessible chemicalsall with a completely automated, black-box,
and efficient design. We demonstrate its utility by generating ∼40
million synthetically accessible, stereochemically accurate compounds
from a single library of 100 000 purchasable molecules and
56 well-characterized chemical reactions.