Isosteric exchange of the acylsulfonamide moiety in Abbott's Bcl-XL protein interaction antagonist.

A multi-component reaction strategy was used for the fast and efficient synthesis of amide isosteres of known Bcl-2 inhibitors capable of disrupting protein-protein interactions. Ugi reaction and a subsequent nucleophilic aromatic substitution reaction provide a versatile path to libraries of compounds similar to Abbott's acylsulfonamides. Modeling arguments are used to explain the inferior activity of the amide as opposed to the sulfonamide series.

Design and modular parallel synthesis of a MCR derived alpha-helix mimetic protein-protein interaction inhibitor scaffold.

A terphenyl alpha-helix mimetic scaffold recognized to be capable of disrupting protein-protein interactions was structurally morphed into an easily amenable and versatile multicomponent reaction (MCR) backbone. The design, modular in-parallel library synthesis, initial cell based biological data, and preliminary in vitro screening for the disruption of the Bcl-w/Bak protein-protein interaction by representatives of the MCR derived scaffold are presented.

Evolutionary chemistry approach toward finding novel inhibitors of the type 2 diabetes target glucose-6-phosphate translocase.

A genetic algorithm (GA), driven by experimentally determined biological activities as a feedback fitness function, was used to propose novel small molecules as inhibitors of glucose-6-phosphate translocase (G6PT) in iterative rounds of evolutionary optimization. A straightforward polymer-supported synthetic sequence was implemented to synthesize molecules proposed by the GA, and the biological activities of the compounds were determined by a microsomal assay. Additional compound design strategies were integrated, such as Tanimoto similarity-based selection of starting materials and transfer of favored structure elements into a new chemical scaffold to identify more active and selective inhibitors.

Novel nonpeptidic inhibitors of HIV-1 protease obtained via a new multicomponent chemistry strategy.

Using a newly developed multicomponent chemistry strategy in combination with structure based drug design, a new class of HIV-1 protease inhibitors has been obtained.