Binding affinity analysis and ADMET prediction of epigallocatechine gallate (EGCG) derivatives for AP-1 protein: a drug target for liver cancer

Abstract

The hepatitis B virus × protein (HBx) of Hepatitis B virus activates AP-1 protein and causes the down regulation of PTEN (full name) and p53 leads to the tumor formation in liver. In this study, the interactions between DNA and AP-1 have been targeted by docking of natural compounds epigallocatechine gallate (EGCG), curcumin, luteoline, genistein, ellagic acid, resveratrol, lupeol, betulinic acid and lycopene. Green Tea (Camellia sinensis) possesses anticancer property. EGCG obtained from green tea shows favourable binding with AP-1 protein among all natural compounds. It is necessary to target DNA binding domain which binds at DNA to induce the expression of p53 and PTEN gene. EGCG have shown interaction at these positions, which may minimize down regulation of p53 and PTEN gene. To increase the binding affinity and bioavailability of EGCG, derivatives have been designed by mimicking the position of H and OH group. One of acetylated derivative EGCG15, made by replacing OH group by OCOCH3 shows better affinity than other derivatives and binds at amino acid Asp 163(G), Ser 278(F), Lys 282(F), Arg 288(F) with six hydrogen bonds and −5.60 kcal/mol energy. Affinity of EGCG with AP-1 protein was greatly enhanced in methoxy derivative EGCG05 which binds at Asp 163, Asp 170, Ser 278, Arg 281, and Arg 288 with eight hydrogen bonds and −6.30 kcal/mol energy (energy complex). Substitution of OH by OCOCH3 increases bioavailability after sequential addition at various positions in EGCG leads in silico. These derivatives also show better affinity, but less than methoxy (OCH3) derivative. Substitution by OCH3 leads to slight increment of 6 % in oral absorption. Substitution by NH2 group leads to no changes in oral absorption or bioavailability. This may lead to inhibition of AP-1 protein which down regulates tumor suppressor gene p53 and PTEN.