Docking analysis of hexanoic acid and quercetin with seven domains of polyketide synthase A provided insight into quercetin-mediated aflatoxin biosynthesis inhibition in Aspergillus flavus

Studies on phytochemicals as anti-aflatoxigenic agents have gained importance including quercetin. Thus, to understand the molecular mechanism behind inhibition of aflatoxin biosynthesis by quercetin, interaction study with polyketide synthase A (PksA) of Aspergillus flavus was undertaken. The 3D structure of seven domains of PksA was modeled using SWISS-MODEL server and docking studies were performed by Autodock tools-1.5.6. Docking energies of both the ligands (quercetin and hexanoic acid) were compared with each of the domains of PksA enzyme. Binding energy for quercetin was lesser that ranged from -7.1 to -5.25 kcal/mol in comparison to hexanoic acid (-4.74 to -3.54 kcal/mol). LigPlot analysis showed the formation of 12 H bonds in case of quercetin and 8 H bonds in hexanoic acid. During an interaction with acyltransferase domain, both ligands showed H bond formation at Arg63 position. Also, in product template domain, quercetin creates four H bonds in comparison to one in hexanoic acid. Our quantitative RT-PCR analysis of genes from aflatoxin biosynthesis showed downregulation of pksA, aflD, aflR, aflP and aflS at 24 h time point in comparison to 7 h in quercetin-treated A. flavus. Overall results revealed that quercetin exhibited the highest level of binding potential (more number of H bonds) with PksA domain in comparison to hexanoic acid; thus, quercetin possibly inhibits via competitively binding to the domains of polyketide synthase, a key enzyme of aflatoxin biosynthetic pathway. Further, we propose that key enzymes from aflatoxin biosynthetic pathway in aflatoxin-producing Aspergilli could be explored further using other phytochemicals as inhibitors.