Computational fishing of new DNA methyltransferase inhibitors from natural products

Maldonado-Rojas, Wilson; Olívero-Verbel, Jesús; Marrero-Ponce, Yovani

doi:10.1016/j.jmgm.2015.04.010

Cited by 30 publications

(22 citation statements)

References 99 publications

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“…The materials and methods described in this study were modified from the studies by Yanuar et al, Syahdi et al, and Maldonado-Rojas et al [11,25,26]. A three-dimensional structure of DNMT1, positive and negative control compounds, and active herbal compounds contained in the HerbalDB were used in this study.…”

Section: Methodsmentioning

confidence: 99%

“…The recent studies have focused on the finding non-nucleoside analog inhibitor candidates from natural sources [8,9]. Natural products are promising non-nucleoside DNMTi candidates because of their relatively low toxicity and high structural diversity [10,11]. The potential of several natural products has been studied; these products have included curcumin [12], epigallocatechin (EGCG) [13], genistein [14], caffeic acid [15], psammaplin A [16], mahanine [17], and laccaic acid [16].…”

Section: Introductionmentioning

confidence: 99%

“…The potential of several natural products has been studied; these products have included curcumin [12], epigallocatechin (EGCG) [13], genistein [14], caffeic acid [15], psammaplin A [16], mahanine [17], and laccaic acid [16]. However, the inhibitory effects of these natural compounds are relatively low [11]. Therefore, a search for more effective DNMTi's from natural compounds is necessary.…”

Section: Introductionmentioning

confidence: 99%

“…The actives were positive controls or compounds that showed inhibitory activity against DNMT1 through in vitro or in vivo tests. Based on the previous research, 25 compounds were chosen as actives [11][12][13][14][15][16][17]. Their structures were obtained in SMILES format from the PubChem website at pubchem.ncbi.nlm.nih.gov [33].…”

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confidence: 99%

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Virtual Screening of Indonesian Herbal Database for Dna Methyltransferase Inhibitors

Bhaskarawilaputraka

Azminah

Erlina

et al. 2017

Asian J Pharm Clin Res

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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...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Virtual Screening of Indonesian Herbal Database for Dna Methyltransferase Inhibitors

Bhaskarawilaputraka

Azminah

Erlina

et al. 2017

Asian J Pharm Clin Res

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“…The molecular parameters used were the following: a grid spacing of 1.000 Å; box size dimensions of Docking validation with biological data. The docking protocol was validated using a test set of 40 molecules, including active and inactive reported inhibitors against dengue virus, as well as reported inhibitors for proteases from other viruses, for comparative purposes [30]. For dengue inhibitors, molecules with IC 50 values less than 15 µM were chosen.…”

Section: In Silico Studiesmentioning

confidence: 99%

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Cabarcas-Montalvo

Maldonado-Rojas

Montes-Grajales

et al. 2016

European Journal of Medicinal Chemistry

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Background: Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS2B/NS3 protease complex is a target for designing specific antivirals due to its importance in viral replication and its high degree of conservation.Methods: NS2B/NS3 protease complex structural information was employed to find small molecules that are capable of inhibiting the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrate and the complex NS2B/NS3 obtained by recombinant DNA techniques, for testing the activity against dengue virus replication, HepG2 cells infected with dengue virus serotype 2 were used. Results: A total of 210,903 small molecules from PubChem were docked in silico to the NS2B/NS3 structure (PDB: 2FOM) to find molecules that were capable of inhibiting this protein complex. Five of the best 500 leading compounds, according to their affinity values (-11.6 and -13.5 kcal/mol), were purchased. The inhibitory protease activity on the recombinant protein and antiviral assays was tested. Conclusions: Chemicals CID54681617, CID54692801 and CID54715399 were strong inhibitors of NS2B/NS3, with IC 50 values (µM) and percentages of viral titer reductions of 19.9, 79.9%; 17.5, 69.8%; and 9.1, 73.9 %, respectively. Multivariate methods applied to the molecular descriptors showed two compounds that were structurally different from other DENV inhibitors. General significance: This discovery opens new possibilities for obtaining drug candidates against Dengue virus.

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Quantitative Structure-Epigenetic Activity Relationships

García-Sánchez

Cruz-Monteagudo

Medina-Franco

2017

Challenges and Advances in Computational Chemistry and Physics

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Computational fishing of new DNA methyltransferase inhibitors from natural products

Cited by 30 publications

References 99 publications

Virtual Screening of Indonesian Herbal Database for Dna Methyltransferase Inhibitors

Virtual Screening of Indonesian Herbal Database for Dna Methyltransferase Inhibitors

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Quantitative Structure-Epigenetic Activity Relationships

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