Virtual Screening of Indonesian Herbal Database for Dna Methyltransferase Inhibitors

Abstract

Objective: DNA hypermethylation is an abnormal epigenetic process catalyzed by DNA methyltransferase 1 (DNMT1). It is also one of the factors that cause non-communicable diseases such as cancer, diabetes, and other metabolic diseases. DNA hypermethylation can be reversed by suppressing DNMT1 activity using a DNMT inhibitor. This study was conducted to seek out inhibitor candidates among natural products. Methods:The search for potential inhibitors was conducted through a virtual screening of the Indonesian Herbal Database using AutoDockVina as docking software. Twenty-five compounds known for their inhibitory activity against DNMT1 were used as actives and as a reference for generating decoys, which was done using the Directory of Useful Decoys, Enhanced. Results:The 12 compounds with binding energies below the cutoff value were cassiamin C (A1), procyanidin B2 (B2), ent-epicatechin-(4alpha->8)-ent-epicatechin (C3), epicatechin-(4beta->8)-epicatechin-3-O-gallate (D4), neorhusflavanone (E5), 3-O-galloylepicatechin-(4beta->6)-epicatechin-3-O-gallate (F6), withanolide (G7), 3-O-galloylepigallocatechin-(4beta->6)-epigallocatechin-3-O-gallate (H8), cyanidin 3-(6''-caffeylsophoroside)-5-glucoside (I9), epifriedelanol (J10), gallocatechin-(4alpha->8)-epicatechin (K11), and scutellarein 7-glucosyl-(1->4)-rhamnoside (L12). A1 had the lowest binding energy of −12.7 kcal/mol, whereas K11 had the highest of −11.5 kcal/mol. Conclusions:The virtual screening yielded five potential DNMT1 inhibitors: Procyanidin B2, ent-epicatechin-(4alpha->8)-ent-epicatechin, epicatechin-(4beta->8)-epicatechin-3-O-gallate, neorhusflavanone, and cyanidin 3-(6''-caffeylsophoroside)-5-glucoside.Keywords: Epigenetic, DNA methyltransferase inhibitor, Indonesian Herbal Database, Virtual screening, AutoDockVina. INTRODUCTIONEpigenetic modification is one of the factors that cause noncommunicable diseases. Living environment, lifestyle, exposure to toxic chemicals, and nutrition may influence an individual's epigenetic profile. Epigenetic modification can alter gene expression [1]. One type of epigenetic modification is DNA methylation. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is the addition of a methyl (CH3) group to the DNA strand, specifically to the fifth carbon atom of a cytosine ring. Methylated cytosine, called 5-methylcytosine, usually occurs to a cytosine base that lies adjacent to a guanine base, at what is called a CpG site. The reason for this name is that cytosine is bonded to guanine through a phosphate bond. These sites normally occur in clusters; an area rich in CpG sites is called a CpG island. CpG islands are usually located near a gene regulator such as a promoter. DNA methylation that affects a gene promoter may repress the transcription of said gene and ultimately its expression. This process of turning a gene on and off through methylation is part of normal eukaryotic cell function [2,3].There are several types of DNMTs. Based on their functions, they can be grouped into two categories: De novo DNMTs...