RESUMO
Through evolution, nature has provided natural products (NPs) as a rich source of diverse bioactive material. Many drug discovery programs have used nature as an inspiration for the design of NP-like compound classes. These concepts are guided by the prevalidated biological relevance of NPs while going beyond the limitations of nature to produce chemical matter that could have unexpected or novel bioactivities. Herein, we discuss, compare, and highlight recent examples of NP-inspired methods with a focus on the pseudo-NP concept.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Compostos Heterocíclicos/química , Hidrocarbonetos Aromáticos/química , Avidina/síntese química , Alcaloides de Cinchona/química , Diterpenos/química , Descoberta de Drogas , Humanos , Compostos Policíclicos/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , PleuromutilinasRESUMO
Natural products (NPs) inspire the design and synthesis of novel biologically relevant chemical matter, for instance through biology-oriented synthesis (BIOS). However, BIOS is limited by the partial coverage of NP-like chemical space by the guiding NPs. The design and synthesis of "pseudo NPs" overcomes these limitations by combining NP-inspired strategies with fragment-based compound design through deâ novo combination of NP-derived fragments to unprecedented compound classes not accessible through biosynthesis. We describe the development and biological evaluation of pyrano-furo-pyridone (PFP) pseudo NPs, which combine pyridone- and dihydropyran NP fragments in three isomeric arrangements. Cheminformatic analysis indicates that the PFPs reside in an area of NP-like chemical space not covered by existing NPs but rather by drugs and related compounds. Phenotypic profiling in a target-agnostic "cell painting" assay revealed that PFPs induce formation of reactive oxygen species and are structurally novel inhibitors of mitochondrial complexâ I.
