Identification of a New Isoindole-2-yl Scaffold as a Qo and Qi Dual Inhibitor of Cytochrome bc1 Complex: Virtual Screening, Synthesis, and Biochemical Assay

Respiratory chain ubiquinol-cytochrome (cyt) c oxidoreductase (cyt bc(1) or complex III) has been demonstrated as a promising target for numerous antibiotics and fungicide applications. In this study, a virtual screening of NCI diversity database was carried out in order to find novel Qo/Qi cyt bc(1) complex inhibitors. Structure-based virtual screening and molecular docking methodology were employed to further screen compounds with inhibition activity against cyt bc(1) complex after extensive reliability validation protocol with cross-docking method and identification of the best score functions. Subsequently, the application of rational filtering procedure over the target database resulted in the elucidation of a novel class of cyt bc(1) complex potent inhibitors with comparable binding energies and biological activities to those of the standard inhibitor, antimycin.