Integrated Bioinformatics Analysis to Study Gallic Acid-Mediated Inhibition of Polyketide Synthase A from Aflatoxin Biosynthesis Pathway of Aspergillus flavus

BackgroundAspergillus flavus is known for producing the potent carcinogenic agent aflatoxin (AFB). To identify and develop anti-aflatoxigenic agents, studies on phytochemicals, including gallic acid, as anti-aflatoxigenic agents have been documented. Thus, interaction studies using in silico tools have been explored to understand the molecular mechanism behind the inhibition of aflatoxin biosynthesis by studying the chemical interactions of gallic acid with polyketide synthase A (PksA) of A. flavus.MethodsThe amino acid sequence of A. flavus polyketide synthase with more than 90% identity was retrieved from NCBI to depict evolutionary relationships using MEGA 6.06 tool. The 3D structure of ligands (hexanoic acid and gallic acid) was built using UCSF Chimera and 3D structure of PksA consisting of seven domains was modelled using a Swiss-Model server followed by docking using Autodock tools-1.5.6. Ramachandran plot analysis for each of the modelled protein structures was carried out for validation. VMD, NAMD and Open-Babel software were used for MD simulation studies. To examine the toxicological properties of phytochemical, Admet SAR was used.ResultsThe binding energy (electrostatic, intermolecular or total internal energy) for gallic acid was lower (- 6.09 to - 4.79 kcal/mol) than that for hexanoic acid (- 5.05 to - 3.36 kcal/mol), a precursor for aflatoxin biosynthesis. During an interaction with the acyl transferase domain of PksA showed the formation of 7-H bonds with gallic acid and 3-H bonds with hexanoic acid. In addition, gallic acid showed stable binding with the active site of PksA, as indicated by steady root mean square deviation through molecular dynamic simulations. The chemistry between gallic acid and polyketide synthase A (PksA) showed that gallic acid/hexanoic acid possesses - 6.09/ - 5.05 binding energy with thioestrase domain.ConclusionWe suggest that gallic acid could be a potential inhibitor for thioestrase and acyl transferase domains of polyketide synthase in aflatoxin-producing Aspergilli.