Identification of a New Isoindole-2-yl Scaffold as a Qo and Qi Dual Inhibitor of Cytochrome bc 1 Complex: Virtual Screening, Synthesis, and Biochemical Assay
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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.
KeywordsCytochrome bc1 complex Virtual screening LibDock Scoring function Qo oxidative site Qi reductive site
The authors are grateful to the Research Council of Tehran University of Medical Sciences for financial support to this research work.
- 8.Nixon GL, Pidathala C, Shone AE, Antoine T, Fisher N, O’Neill PM, Ward SA, Biagini GA (2013) Targeting the mitochondrial electron transport chain of Plasmodium falciparum: new strategies towards the development of improved antimalarials for the elimination era. Future Med Chem 13:1573–1591CrossRefGoogle Scholar
- 9.Nixon GL, Ward SA, O’Neill PM, Biagini GA (2014) Inhibitors of the Plasmodium mitochondrial respiratory chain. Encyclopedia of Malaria. pp:1–18Google Scholar
- 10.Lucumi E, Darling C, Jo H, Napper AD, Chandramohanadas R, Fisher N, Shone AE, Jing H, Ward SA, Biagini GA, DeGrado WF, Diamond SL, Greenbaum DC (2010) Discovery of potent small-molecule inhibitors of multidrug-resistant Plasmodium falciparum using a novel miniaturized high-throughput luciferase-based assay. Antimicrob Agents Chemother 9:3597–3604CrossRefGoogle Scholar
- 15.Srivastava IK, Morrisey JM, Darrouzet E, Daldal F, Vaidya AB (1999) Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Mol Micro biol 33:704–711Google Scholar
- 24.Gao X, Wen X, Esser L, Quinn B, Yu L, Yu CA, Xia D (2003) Structural basis for the quinone reduction in the bc1 complex: a comparative analysis of crystal structures of mitochondrial cytochrome bc1 with bound substrate and inhibitors at the Qi site. Biochemistry 42(30):9067–9080CrossRefGoogle Scholar
- 25.Huang L, Cobessi D, Tung EY, Berry EA (2005) Binding of the respiratory chain inhibitor antimycin to the mitochondrial bc 1 complex: a new crystal structure reveals an altered intramolecular hydrogen-bonding pattern description of the active site of bc 1 complex. J Mol Biol 351:573–597CrossRefGoogle Scholar
- 26.Discovery studio modeling environment, release 4.1 (2014). Accelrys Software Inc. San DiegoGoogle Scholar