Toward an ab initio fragment database for bioisosterism: dependence of QCT properties on level of theory, conformation, and chemical environment.

The goal of this work is to assess the scope and suitability of atomic and bond properties for use in a bioisostere fragment database. This database will contain fragment descriptors that can be used to represent portions of larger molecules and similarity in properties between fragments, which will then be used to find bioisosteric replacements in future work. Seventeen common organic fragments relevant to drug design featured as "linker groups" that were capped by two terminal groups. Each terminal group could be one of the set of 12 possible sets: 10 aromatic heterocycles, a phenyl ring, or an ethyl. This enabled a systematic investigation of the chemical environment, enriched with conformational flexibility within the linker group, for a total of 307 different atoms. Five different levels of theory were investigated. This work paves the way to the construction of a quantum mechanical bioisosteric fragment database, for which transferability of stored fragment properties is of fundamental importance.