Molecular interaction of antifungal compounds with fungal type I Polyketide synthase and preventing hepatocarcinogenesis

Abstract

Background: The type I fungal iterative Polyketide synthase (PKS) is found in many toxigenic Aspergillus species. PKS is an important biological non- reducing (NR) type enzymes. It possesses highly active Acyl Carrier Protein (ACP) domain that is implicated in thiol ester-bound intermediates in involved in fungal polyketides, fatty acids and other non-ribosomal peptides formation. These natural polyketide and fatty acids are participated in formation of aflatoxin biosynthesis. These aflatoxins are highly responsible for hepatocarcinhgenesis (HCC), one of commonest cancer among humans living in tropical regions. The HCC has also been shown the synergetic effect with viral infections especially hepatitis B. The risk of HCC is drastically increased under episodic exposure of aflatoxin contaminated feed and hepatitis B that can be fatal if delay in diagnosis and proper treatment. Methods & Materials: The ACP domain as 3D coordinates 2KR5.pdb of polyketide synthase of Aspergillus parasiticus is taken from RCSB. The requisite antifungal ligand files for docking purpose i.e. neoeriocitrin (CID: 114627), blasticidin-S (CID: 16380), blasticidin-S hydrochloride (CID: 258) and pipernomaline (CID: 9974595) protein were retrieved from PubChem Database. The protein preparation, ligand library preparation, sites identification and docking (LibDock Score) were performed by using dynamic software Discovery Studio version 3.5. Results: In the three different sites, site 1 (x: -7.589; y: -2.949; z: 4.007) shown the most effective docking results. At this site 1, the highest LibDock score of 160.282 for 2KR5- neoeriocitrin had shown the successful inhibition of polyketide synthase. Lys4, Asp80, Gly84, Gly86, Asp87 and Gly89 are the amino acides of the protein that are interacted with neoeriocitrin. Conclusion: The Computational study and prediction of three different active sites in ACP domain of PKS of Aspergillus parasiticus had shown the successful interaction with proper ligands. The neoeriocitrin and similar other organic compounds are the very effective flavonoid found in grape fruits that can essentially use in treating HCC and Hepatitis patients.