Vital residues-orientated rational design of butenolide inhibitors targeting Of ChtI

In this study, we employed a rational approach to design and synthesize a library of butenolide analogues (Ia-f andIIa-f) targeting Trp107, utilizing reported piperonyl butenolide as lead compound. Notably, the most compoundsIIa-f (R2 = NO2) exhibited slightly higher inhibitory potency againstOf ChtI compared to compoundsIa-f (R2 = Br). Molecular mechanism studies unveiled a crucial hydrogen bond interaction between the NO2 group and Trp107, explaining the enhanced binding affinities. CompoundsIIe andIIf, both bearing NO2 on the benzene ring at the R2 position, displayed the highest inhibitory activity, withKi values of 0.87 and 0.68  μM, respectively. Our findings highlight the potential of designing inhibitors with high enzymatic activity by structurally optimizing compounds based on the distinct interaction modes with crucial residues in the binding cavity ofOf ChtI.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research