Structure-based virtual screening, pharmacokinetic prediction, molecular dynamics studies for the identification of novel EGFR inhibitors in breast cancer

Anbuselvam, Mohan; Easwaran, Murugesh; Meyyazhagan, Arun; Anbuselvam, Jeeva; Bhotla, Haripriya Kuchi; Sivasubramanian, Mathumathy; Annadurai, Yamuna; Kaul, Tanushri; Pappuswamy, Manikantan; Balasubramanian, Balamuralikrishnan

doi:10.1080/07391102.2020.1777899

Cited by 11 publications

(3 citation statements)

References 30 publications

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“…Based on molecular docking, molecular dynamics simulations were used to further investigate the conformational changes during the binding of the major compounds to the active protein. The RMSD method was used to determine the average deviation of the ligand-enzyme receptor conformation within 50 ns thus assessing the steady state of the ligand-receptor system [ 57 ]. Figure 7 A shows that the RMSD values of the (+)-catechin-tyrosinase system and (−)-epicatechin-tyrosinase system exhibited an increasing trend at first, then decreased and finally reached the basic equilibrium during 50 ns, indicating that the ligand is bound to the active site of tyrosinase and the whole system was stable.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Promotive Effects and Mechanisms of Different Polyphenolic Extracts from Prinsepia utilis Royle Seed Shell on Tyrosinase

Zheng

Zhang

et al. 2022

Foods

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Prinsepia utilis Royle (P. utilis) is commonly used as a food ingredient and herbal medicine according to folk records, yet little research has been done on the seed shell, a processing waste. The aim of this study was to investigate the distribution of polyphenolic components and the tyrosinase activation activity of different extracts from the seed shell by UHPLC-ESI-HRMS/MS, in vitro tyrosinase activity assay, molecular docking and molecular dynamics. A total of 16 phytochemicals were identified, of which (+)-catechin and (−)-epicatechin were the major polyphenolic compounds. Both the esterified and insoluble bound polyphenols exhibited tyrosinase activation activity, and the esterified polyphenols showed better tyrosinase activation activity. (+)-Catechin and (−)-epicatechin might be the main activators of tyrosinase, both of which may act as substrate to affect tyrosinase activity. By molecular docking and molecular dynamics simulation studies, (+)-catechin and (−)-epicatechin can be efficiently and stably bound to the tyrosinase active site through hydrogen bonds, van der Waals forces and π-bonds. The results of this study may not only provide a scientific basis for exploring P. utilis seed shell as a potential activator of tyrosinase, but also contribute to the high value utilization of P. utilis processing by-products.

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Section: Resultsmentioning

confidence: 99%

Exploring the Promotive Effects and Mechanisms of Different Polyphenolic Extracts from Prinsepia utilis Royle Seed Shell on Tyrosinase

Zheng

Zhang

et al. 2022

Foods

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“…EGFR is also a well-known curative target for TNBC. 28 , 29 Similarly, Livasy reported that 70–78% of patients with TNBC highly express EGFR. Hence, EGFR might be a possible therapeutic target in TNBC.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the Mechanism of the ChaiShao Shugan Formula Against Triple-Negative Breast Cancer

Fan,

Huang,

Liu

et al. 2024

DDDT

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Background:The ChaiShao Shugan Formula (CSSGF) is a traditional Chinese medicine formula with recently identified therapeutic value in triple-negative breast cancer (TNBC). This study aimed to elucidate the underlying mechanism of CSSGF in TNBC treatment. Methods: TNBC targets were analyzed using R and data were from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The major ingredients and related protein targets of CSSGF were explored via the Traditional Chinese Medicine Systems Pharmacology database, and an ingredient-target network was constructed via Cytoscape to identify hub genes. The STRING database was used to construct the PPI network. GO and KEGG enrichment analyses were performed via R to obtain the main targets. The online tool Kaplan-Meier plotter was used to identify the prognostic genes. Molecular docking was applied to the core target genes and active ingredients. MDA-MB-231 and MCF-7 cell lines were used to verify the efficacy of the various drugs. Results: A total of 4562 genes were screened as TNBC target genes. The PPI network consisted of 89 nodes and 845 edges. Our study indicated that quercetin, beta-sitosterol, luteolin and catechin might be the core ingredients of CSSGF, and EGFR and c-Myc might be the latent therapeutic targets of CSSGF in the treatment of TNBC. GO and KEGG analyses indicated that the anticancer effect of CSSGF on TNBC was mainly associated with DNA binding, transcription factor binding, and other biological processes. The related signaling pathways mainly involved the TNF-a, IL-17, and apoptosis pathways. The molecular docking data indicated that quercetin, beta-sitosterol, luteolin, and catechin had high affinity for EGFR, JUN, Caspase-3 and ESR1, respectively. In vitro, we found that CSSGF could suppress the expression of c-Myc or promote the expression of EGFR. In addition, we found that quercetin downregulates c-Myc expression in two BC cell lines. Conclusion:This study revealed the effective ingredients and latent molecular mechanism of action of CSSGF against TNBC and confirmed that quercetin could target c-Myc to induce anti-BC effects.

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“…Then, the refined target structure was taken into Glide receptor grid generation panel for the generation of the three-dimensional (3D) grid box with a size of 20 × 20 × 20 Å with van der Waals scaling factor set at 1.0 and partial charge cut-off at 0.25. A total of 300,000 compounds were downloaded from Zinc database in the form of SDF and the compounds structure were imported into ligprep panel and preparation was performed [12,13]. Here we applied some crucial criteria for ligand preparation including i) Ligands ionization points at pH 7.0 ± 2.0 and the stereoisomers were generated for each ligand structure, ii) compounds structural energy minimization using the OPLS3 force field, (iii) the desalt-option were generated, (iv) tautomer were generated for all conformers, (v) one lowest energy conformer was generated per ligand.…”

Section: Virtual Screeningmentioning

confidence: 99%

Structure-Based Virtual Screening, Insilico Docking, ADME Prediction, and Molecular Dynamics Studies for Identification of Potential NMT Inhibitors Against Malaria

Anbuselvam¹,

Katherine

Anbuselvam

et al. 2021

Preprint

Self Cite

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One of the major public health problems globally, malaria, is mainly caused protozoan parasites from the genus Plasmodium, and commonly spreads to people through the bites of infected female mosquitoes of the genus Anopheles. Strategies for treatment, prevention, and control are available for malaria but the eradication of malaria still poses great challenge due to plasmodium’s drug resistance over the past decades. Development of novel antimalarial drugs remains a significant task to protect people from malaria. N-Myristoyl transferase is responsible for the N-Myristoylation catalysis process and the survival of Plasmodium species. Thus, it is considered a therapeutic drug target in protozoans and was recently validated as a significant target for Plasmodium vivax. In this present scenario, we endeavour to identify effective NMT inhibitors to prevent the onset of malaria in the human species. Initially, the structure-based virtual screening was executed against ZINC database and four potential candidates for NMT were identified. Furthermore, the four identified compounds were subjected to ADME prediction and all the four compounds found within adequate range with predicted ADME properties. Eventually, we conducted the molecular dynamics simulation to investigate the binding stability of top three protein-ligand complexes at different time scale by employing the tool Desmond. The molecular dynamics simulation studies revealed the protein-ligand complexes were stable throughout the entire simulation. Besides, we noticed that the residues ASN 365, PHE 103 and HIS 213 of NMT were crucially involved in the formation of various intermolecular interactions, significantly contributing to the stability of protein-ligand complexes. From this computational investigation, we suggest that the three identified potential compounds are extremely useful for further lead optimization and drug development.

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Structure-based virtual screening, pharmacokinetic prediction, molecular dynamics studies for the identification of novel EGFR inhibitors in breast cancer

Cited by 11 publications

References 30 publications

Exploring the Promotive Effects and Mechanisms of Different Polyphenolic Extracts from Prinsepia utilis Royle Seed Shell on Tyrosinase

Exploring the Promotive Effects and Mechanisms of Different Polyphenolic Extracts from Prinsepia utilis Royle Seed Shell on Tyrosinase

Unveiling the Mechanism of the ChaiShao Shugan Formula Against Triple-Negative Breast Cancer

Structure-Based Virtual Screening, Insilico Docking, ADME Prediction, and Molecular Dynamics Studies for Identification of Potential NMT Inhibitors Against Malaria

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