The design, synthesis, and virtual screening of spirocyclic ketals as prospecting library members.

摘要

I. Design and Synthesis of Spirocyclic Ketals as Prospecting Library Members. Forward design is a rapid and facile process for designing novel and diverse core scaffolds for inclusion in a prospecting (lead discovery) library. To expand the diversity of compounds that can be synthesized combinatorially, the principles of forward design were used to devise a synthesis of two spirocyclic ketal scaffolds for inclusion in a prospecting library. The scaffolds are novel, rigid, drug-like, readily diversified with commercially available inputs, and accessible in high yield and purity. The synthesis of monomer-scan libraries of the two spirocyclic ketal scaffolds was performed using both solid- and solution-phase combinatorial techniques to demonstrate the generality of the synthesis.; II. Virtual Screening of Combinatorial Libraries Using a Vector Comparison Approach. A chemist, using the principles of combinatorial chemistry, can conceive of many more compounds to synthesize than time and matter in the universe can support. Virtual screening is the process of using computational techniques to reduce a library containing an unmanageable number of compounds to a limited number of potentially promising compounds for the target of interest. Caveat is a similarity search program that finds conformational mimics of a target molecule based on the vector relationships between substitutable bonds. A process for rapid and facile generation of Caveat source databases of virtually any class of molecule was devised in order to further develop Caveat as tool for virtual screening. A database, named Gemini, was constructed based on 14 scaffolds that have been synthesized combinatorially. Screening of the database using Caveat against a variety of common peptide secondary structures demonstrated the ability of Gemini to provide synthetically accessible mimics of a conformationally diverse set of targets.