Development of a Graphical User Interface Application to Identify Marginal and Potent Ligands for Estrogen Receptor Alpha

Yuniarti, Nunung; Mungkasi, Sudi; Yuliani, Sri Hartati; Istyastono, Enade Perdana

doi:10.22146/ijc.34561

Cited by 4 publications

(9 citation statements)

References 21 publications

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“…These values were equal to inhibition constant (Ki) values in subpicomolar [21] indicating that the pentapeptide AEYTR was a potent AChEI. In vitro tests will be performed as the ultimate confirmation of the in silico results [18,26] and discussed elsewhere.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Structure-Based Design and Molecular Dynamics Simulations of Pentapeptide AEYTR as a Potential Acetylcholinesterase Inhibitor

Prasasty

Istyastono

2020

Indones. J. Chem.

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Structure-based virtual screening protocol to identify potent acetylcholinesterase inhibitors was retrospectively validated. The protocol could be employed to examine the potential of designed compounds as novel acetylcholinesterase inhibitors. In a research project designing short peptides as acetylcholinesterase inhibitors, peptide AEYTR emerged as one of the potential inhibitors. This article presents the design of AEYTR assisted by the validated protocol and guided by literature reviews followed by molecular dynamics studies to examine the interactions of the pentapeptide in the binding pocket of the acetylcholinesterase enzyme. The molecular dynamics simulations were performed using YASARA Structure in Google Cloud Platform. The peptide AEYTR was identified in silico as a potent acetylcholinesterase inhibitor with the average free energy of binding (DG) of -19.138 kcal/mol.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Structure-Based Design and Molecular Dynamics Simulations of Pentapeptide AEYTR as a Potential Acetylcholinesterase Inhibitor

Prasasty

Istyastono

2020

Indones. J. Chem.

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“…The EF and AUC values showed that the virtual screening method using pharmacophore model 2 was an excellent screening model. The EF and AUC values were worse than the SBVS protocol reported by Yuniarti et al [27], but it was still better than the results reported by Setiawati et al [28], and also the EF and AUC values of the SBVS protocol used to identify ligands for ERα in DUD-E (EF = 15.4, AUC = 0.675) [29]. Therefore, the virtual screening of 186 AIACs and AMACs compounds was performed using model 2.…”

Section: Model Preparation and Validationmentioning

confidence: 89%

Ligand Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies of Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) to Discover Novel Estrogen Receptors Alpha (ERα) Inhibitor

et al. 2020

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The estrogen receptor alpha (ERα) plays an important role in breast development and pro-proliferation signal activation in the normal and cancerous breast. The ERα inhibitors were potentially active as cytotoxic agents against breast cancer. This study was conducted in order to find Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) as hits of ERα inhibitor. A training set of 17 selected ERα inhibitors was used to create 10 pharmacophore models using LigandScout 4.2. The pharmacophore models were validated using 383 active compounds as positive data and 20674 decoys as negative data obtained from DUD.E. Model 2 was found as the best pharmacophore model and consisted of three types of pharmacophore features, viz. one hydrophobic, one hydrogen bond acceptor, and aromatic interactions. Model 2 was utilized for ligand-based virtual screening 186 of AIACs, AMACs, intermediates, and Mannich base derivative compounds. The hits obtained were further screened using molecular docking, analyzed using drug scan, and tested for its synthesis accessibility. Fourteen compounds were fulfilled as hits in pharmacophore modeling, in which 10 hits were selected by molecular docking, but only seven hits met Lipinski’s rule of five and had medium synthesis accessibility. In conclusion, seven compounds were suggested to be potentially active as ERα inhibitors and deserve to be synthesized and further investigated.

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“…The main material for the docking simulations was the crystal structure of the Wild-type PfDHFR complexed with pyrimethamine (PDB:3QGT) [3]. Computation for the docking simulations was performed in the same machine used by Yuniarti et al [14].…”

Section: Methodsmentioning

confidence: 99%

Docking-Guided 3D-QSAR Studies of 4-Aminoquinoline-1,3,5-triazines as Inhibitors for <i>Plasmodium falciparum</i> Dihydrofolate Reductase

et al. 2020

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Mutations in Plasmodium falciparum dihydrofolate reductase (PfDHFR), together with other mutations, hinder malaria elimination in Southeast Asia due to multiple drug resistance. In this article, molecular docking-guided three-dimensional (3D) quantitative structure-activity relationship (QSAR) analysis of 4-aminoquinoline-1,3,5-triazines as inhibitors for the wild-type (WT) PfDHFR to identify the molecular determinants of the inhibitors binding are presented. Compounds 4-aminoquinoline-1,3,5-triazines were reported promising to be developed as the non-resistant drugs. The 3D-QSAR analysis resulted in the best model with the R2 and Q2 values of 0.881 and 0.773, respectively. By correlating the molecular interaction fields (MIFs) of the best model to the docking pose employed to guide the 3D-QSAR analysis, S108 residue of the WT-PfDHFR was unfortunately recognized as one of the molecular determinants. Since the S108 residue is one of the mutation points of the PfDHFR mutants, the subsequent design strategy should modify the morpholine moiety to avoid the interaction with the S108 residue of the WT-PfDHFR.

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Development of a Graphical User Interface Application to Identify Marginal and Potent Ligands for Estrogen Receptor Alpha

Cited by 4 publications

References 21 publications

Structure-Based Design and Molecular Dynamics Simulations of Pentapeptide AEYTR as a Potential Acetylcholinesterase Inhibitor

Structure-Based Design and Molecular Dynamics Simulations of Pentapeptide AEYTR as a Potential Acetylcholinesterase Inhibitor

Ligand Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies of Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) to Discover Novel Estrogen Receptors Alpha (ERα) Inhibitor

Docking-Guided 3D-QSAR Studies of 4-Aminoquinoline-1,3,5-triazines as Inhibitors for <i>Plasmodium falciparum</i> Dihydrofolate Reductase

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