scholarly journals Understanding the binding of inhibitors of matrix metalloproteinases by molecular docking, quantum mechanical calculations, molecular dynamics simulations, and a MMGBSA/MMBappl study

2015 ◽  
Vol 11 (4) ◽  
pp. 1041-1051 ◽  
Author(s):  
Tanya Singh ◽  
Olayiwola Adedotun Adekoya ◽  
B. Jayaram
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Important Class ◽  
Matrix Metalloproteinase Inhibitors ◽  
Metalloproteinase Inhibitors ◽  
Dynamics Simulations

A computationally tractable pathway which helped in understanding the binding of matrix metalloproteinase inhibitors against an important class of MMPs is presented in this article.

Structure-based molecular insights into matrix metalloproteinase inhibitors in cancer treatments

2021 ◽  
pp. 00-00
Author(s):  
Haili Lin ◽  
Peng Xu ◽  
Mingdong Huang
Keyword(s):  
Clinical Trials ◽  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Protease Inhibitors ◽  
Anticancer Agents ◽  
Cancer Development ◽  
Pharmaceutical Companies ◽  
Matrix Metalloproteinase Inhibitors ◽  
Cancer Treatments ◽  
Metalloproteinase Inhibitors

Protease inhibitors are of considerable interest as anticancer agents. Matrix metalloproteinases (MMPs) were the earliest type of proteases considered as anticancer targets. The developments of MMP inhibitors (MMPIs) by pharmaceutical companies can be dated from the early 1980s. Thus far, none of the over 50 MMPIs entering clinical trials have been approved. This work summarizes the reported studies on the structure of MMPs and complexes with ligands and inhibitors, based on which, the authors analyzed the clinical failures of MMPIs in a structural biological manner. Furthermore, MMPs were systematically compared with urokinase, a protease-generating plasmin, which plays similar pathological roles in cancer development; the reasons for the clinical successes of urokinase inhibitors and the clinical failures of MMPIs are discussed.

Investigations on the mechanisms of interactions between matrix metalloproteinase 9 and its flavonoid inhibitors using a combination of molecular docking, hybrid quantum mechanical/molecular mechanical calculations, and molecular dynamics simulations

2014 ◽  
Vol 92 (9) ◽  
pp. 821-830 ◽  
Author(s):  
Zhi-Guang Zhou ◽  
Qi-Zheng Yao ◽  
Dong Lei ◽  
Qing-Qing Zhang ◽  
Ji Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Biological Activities ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Free Energies ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Binding Free Energies

Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM−Poisson–Boltzmann surface area (PBSA) and the experimental −log(EC50) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM−PBSA method, the QM/MM−PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid−MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn−O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid−MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein−ligand interactions. This paper may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.

scholarly journals A molecular dynamics simulation study on the propensity of Asn-Gly-containing heptapeptides towards β-turn structures: Comparison with ab initio quantum mechanical calculations

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243429
Author(s):  
Dimitrios A. Mitsikas ◽  
Nicholas M. Glykos
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Molecular Dynamics Simulations ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Type I ◽  
Quantum Mechanical Calculations ◽  
Water Solvent ◽  
Simulation Protocol ◽  
Dynamics Simulations

Both molecular mechanical and quantum mechanical calculations play an important role in describing the behavior and structure of molecules. In this work, we compare for the same peptide systems the results obtained from folding molecular dynamics simulations with previously reported results from quantum mechanical calculations. More specifically, three molecular dynamics simulations of 5 μs each in explicit water solvent were carried out for three Asn-Gly-containing heptapeptides, in order to study their folding and dynamics. Previous data, based on quantum mechanical calculations within the DFT framework have shown that these peptides adopt β-turn structures in aqueous solution, with type I’ β-turn being the most preferred motif. The results from our analyses indicate that at least for the given systems, force field and simulation protocol, the two methods diverge in their predictions. The possibility of a force field-dependent deficiency is examined as a possible source of the observed discrepancy.

scholarly journals Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

2020 ◽  
Vol 13 (6) ◽  
pp. 113
Author(s):  
Antonio Laghezza ◽  
Luca Piemontese ◽  
Leonardo Brunetti ◽  
Alessia Caradonna ◽  
Mariangela Agamennone ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Bone Remodeling ◽  
Cancer Progression ◽  
Tumor Invasion ◽  
Standard Care ◽  
Computational Analysis ◽  
Matrix Metalloproteinase Inhibitors ◽  
Metalloproteinase Inhibitors

Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we designed and characterized potent MMP-2/MMP-9 inhibitors. This is a promising approach to develop and clinically translate inhibitors that could be used in combination with standard care therapy for the treatment of skeletal malignancies.

Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury☆

2006 ◽  
Vol 37 (4) ◽  
pp. 422-430 ◽  
Author(s):  
S FLIGIEL ◽  
T STANDIFORD ◽  
H FLIGIEL ◽  
D TASHKIN ◽  
R STRIETER ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Matrix Metalloproteinases ◽  
Lung Injury ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase Inhibitors ◽  
Metalloproteinase Inhibitors

Virtual Screening: Using Molecular Docking and 3D-QSAR Analysis of Matrix Metalloproteinase Inhibitors

2013 ◽  
pp. n/a-n/a
Author(s):  
Laura Amador-Falcón ◽  
Daniela Rodríguez-Clavijo ◽  
Rosa Baldiris-Ávila ◽  
Verónica Valdiris-Ávila ◽  
Guillermo Salgado-Morán ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Matrix Metalloproteinase ◽  
3D Qsar ◽  
Matrix Metalloproteinase Inhibitors ◽  
Qsar Analysis ◽  
Metalloproteinase Inhibitors
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