Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template

In this paper, we describe a lead transformation tool,
NEAT (Novel and Electronically
equivalent Aromatic Template), which can
help identify novel aromatic rings that are estimated to have similar
electrostatic potentials, dipoles, and hydrogen bonding capabilities
to a query template; hence, they may offer similar bioactivity profiles.
In this work, we built a comprehensive heteroaryl database, and precalculated
high-level quantum mechanical (QM) properties, including electrostatic
potential charges, hydrogen bonding ability, dipole moments, chemical
reactivity, and othe properties. NEAT bioisosteric similarities are
based on the electrostatic potential surface calculated by Brood,
using the precalculated QM ESP charges and other QM properties. Compared
with existing commercial lead transformation software, (1) NEAT is
the only one that covers the comprehensive heteroaryl chemical space,
and (2) NEAT offers a better characterization of novel aryl cores
by using high-evel QM properties that are relevant to molecular interactions.
NEAT provides unique value to medicinal chemists quickly exploring
the largely uncharted aromatic chemical space, and one successful
example of its application is discussed herein.