Structure-Guided Identification of DNMT3B Inhibitors

Newton, Ana S.; Faver, John C.; Micevic, Goran; Muthusamy, Viswanathan; Kudalkar, Shalley N.; Bertoletti, Nicole; Anderson, Karen S.; Bosenberg, Marcus W.; Jorgensen, William

doi:10.1021/acsmedchemlett.0c00011

Cited by 15 publications

(10 citation statements)

References 24 publications

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“…In this study, we conducted a more efficient VS of new scaffolds of TNKS inhibitors compared with traditional screening methods after first completing screening model training. Simple docking methods, such as rigid body or induced fit docking, have been used in many studies [ 15 , 35 , 36 ] and may easily be biased because of their oversimplified simulation systems ( Figure S2 ). The pharmacophore method is used to identify potential compounds through pharmacophores, which are built with ligand or protein features, and the screened compounds are deemed potential compounds if they can fit the pharmacophores.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer

Chang

Pan

et al. 2022

Biomedicines

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The abnormal Wnt signaling pathway leads to a high expression of β-catenin, which causes several types of cancer, particularly colorectal cancer (CRC). The inhibition of tankyrase (TNKS) activity can reduce cancer cell growth, invasion, and resistance to treatment by blocking the Wnt signaling pathway. A pharmacophore search and pharmacophore docking were performed to identify potential TNKS inhibitors in the training databases. The weighted MM/PBSA binding free energy of the docking model was calculated to rank the databases. The reranked results indicated that 26.98% of TNKS inhibitors that were present in the top 5% of compounds in the database and near an ideal value ranked 28.57%. The National Cancer Institute database was selected for formal virtual screening, and 11 potential TNKS inhibitors were identified. An enzyme-based experiment was performed to demonstrate that of the 11 potential TNKS inhibitors, NSC295092 and NSC319963 had the most potential. Finally, Wnt pathway analysis was performed through a cell-based assay, which indicated that NSC319963 is the most likely TNKS inhibitor (pIC50 = 5.59). The antiproliferation assay demonstrated that NSC319963 can decrease colorectal cancer cell growth; therefore, the proposed method successfully identified a novel TNKS inhibitor that can alleviate CRC.

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Section: Discussionmentioning

confidence: 99%

Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer

Chang

Pan

et al. 2022

Biomedicines

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“…Nanaomycin A, the specific inhibitor of DNMT3b, upregulates the mRNA and protein expression of SCARB1 in foam cells [302]. Additional DNMT3B inhibitors may also be tested to affect SCARB1 expression [318].…”

Section: Transcriptional Regulation Of Expressionmentioning

confidence: 99%

Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis

Rozhkova

Дмитриева

Nosova

et al. 2021

JCDD

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Atheroprotective properties of human plasma high-density lipoproteins (HDLs) are determined by their involvement in reverse cholesterol transport (RCT) from the macrophage to the liver. ABCA1, ABCG1, and SR-BI cholesterol transporters are involved in cholesterol efflux from macrophages to lipid-free ApoA-I and HDL as a first RCT step. Molecular determinants of RCT efficiency that may possess diagnostic and therapeutic meaning remain largely unknown. This review summarizes the progress in studying the genomic variants of ABCA1, ABCG1, and SCARB1, and the regulation of their function at transcriptional and post-transcriptional levels in atherosclerosis. Defects in the structure and function of ABCA1, ABCG1, and SR-BI are caused by changes in the gene sequence, such as single nucleotide polymorphism or various mutations. In the transcription initiation of transporter genes, in addition to transcription factors, long noncoding RNA (lncRNA), transcription activators, and repressors are also involved. Furthermore, transcription is substantially influenced by the methylation of gene promoter regions. Post-transcriptional regulation involves microRNAs and lncRNAs, including circular RNAs. The potential biomarkers and targets for atheroprotection, based on molecular mechanisms of expression regulation for three transporter genes, are also discussed in this review.

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“…In a recent study, docking-based screening was performed to identify potential inhibitors against isocitrate lyase of Mtb [25]. There are several other studies in which docking-based virtual screening has been successfully applied for the identification of novel inhibitors [26][27][28][29][30]. The Molecular Mechanics Poisson-Boltzman Surface Area (MM/PBSA) method is used to estimate binding affinity of protein-ligand complexes predicted by the molecular docking.…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Inhibitors of Type-I Mycobacterium Tuberculosis Fatty Acid Synthase Using Docking-Based Virtual Screening and Molecular Dynamics Simulation

Singh

Mao

2021

Applied Sciences

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Mycobacterial fatty acid synthase type-I (FAS-I) has an important role in the de novo synthesis of fatty acids, which constitute a major component of the cell wall. The essentiality of FAS-I in the survival and growth of mycobacterium makes it an attractive drug target. However, targeted inhibitors against Mycobacterial FAS-I have not been reported yet. Recently, the structure of FAS-I from Mycobacterium tuberculosis was solved. Therefore, in a quest to find potential inhibitors against FAS-I, molecular docking-based virtual screening and molecular dynamics simulation were done. Subsequently, molecular dynamic simulations based on binding free energy calculations were done to gain insight into the predicted binding mode of putative hits. The detailed analysis resulted in the selection of four putative inhibitors. For compounds BTB14738, RH00608, SPB02705, and CD01000, binding free energy was calculated as −72.27 ± 12.63, −68.06 ± 11.80, −63.57 ± 12.22, and −51.28 ± 13.74 KJ/mol, respectively. These compounds are proposed to be promising pioneer hits.

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Structure-Guided Identification of DNMT3B Inhibitors

Cited by 15 publications

References 24 publications

Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer

Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer

Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis

Identification of Novel Inhibitors of Type-I Mycobacterium Tuberculosis Fatty Acid Synthase Using Docking-Based Virtual Screening and Molecular Dynamics Simulation

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