In-silico strategies for identification of potent inhibitor for MMP-1 to prevent metastasis of breast cancer

Matrix Metalloproteinase-1 (MMP-1) has been often upregulated in advanced breast cancers, known to participate in ECM degradation, migration, invasion, thus leading to metastasis. Due to these effects, the condition is often reported to inversely correlate with survival in advanced breast cancers. I...

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Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2021-12, Vol.39 (18), p.7274-7293
Main Authors: Shunmuga Priya, Velu, Pradiba, Dhinakararajan, Aarthy, Murali, Singh, Sanjeev Kumar, Achary, Anant, Vasanthi, Mani
Format: Article
Language:English
Subjects:
breast cancer
Breast Neoplasms - drug therapy
Female
Humans
Ligands
Matrix Metalloproteinase 1
Matrix Metalloproteinase Inhibitors - pharmacology
metastasis
MMP-1
molecular docking
Molecular Docking Simulation
Molecular Dynamics Simulation
Neoplasm Metastasis - prevention & control
phytochemicals
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Summary:Matrix Metalloproteinase-1 (MMP-1) has been often upregulated in advanced breast cancers, known to participate in ECM degradation, migration, invasion, thus leading to metastasis. Due to these effects, the condition is often reported to inversely correlate with survival in advanced breast cancers. In the present study, in-silico method was adopted based on selective non zinc binding inhibitors of MMP-1. ADME properties were predicted for PASS filtered compounds and docking calculations were performed using Glide XP and IFD protocols of Schrodinger program. We identified six ligands as potent inhibitors and validated by observing structures and the interactions of MMP-1. The identified hits were validated using molecular dynamics simulation studies. Electronic structure analysis was performed for two top hit compounds myricetin and quercetin using density function theory (DFT) at B3LYP/6-31**G level to understand their molecular reactivity. Finally, one compound myricetin has emerged as the structurally stable compound with −7.801 kcal/mol and reasonable pose inside the binding site. Molecular dynamics results indicated that myricetin forms a stable interaction with the key amino acid residues such as Glu209, Glu219, Tyr240 and Pro238. In addition, it did not form any binding with the catalytic zinc at its active site. The interaction pattern of myricetin at its substrate binding site exhibited to be potent MMP-1 inhibitor. DFT study also showed that it has more potent inhibitory effect and solubility. These factors altogether show that myricetin could be considered as the best among the compounds evaluated in inhibiting MMP-1 thereby preventing metastasis of breast cancer. Communicated by Ramaswamy H. Sarma
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2020.1810776