title: Exploring aromatic chemical space with NEAT: novel and electronically equivalent aromatic template.
abstract: 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.
authors.affiliation: Pfizer Worldwide Research and Development, 620 Memorial Drive, Cambridge, Massachusetts 02139, USA. meihua.tu@pfizer.com
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Brajesh K
authors.initials: BK
authors.lastname: Rai
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.forename: Mary
authors.initials: M
authors.lastname: Didiuk
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: John
authors.initials: J
authors.lastname: Benbow
authors.forename: Cristiano R W
authors.initials: CR
authors.lastname: Guimarães
authors.forename: Scot
authors.initials: S
authors.lastname: Mente
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hayward
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
mesh_terms: D055808:Drug Discovery; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D008956:Models, Chemical; D010879:Piperazines / Q000737:chemistry; D011687:Purines / Q000737:chemistry; D011789:Quantum Theory; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000737:chemistry
chemical_list: D006841:Hydrocarbons, Aromatic; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate