Molecular dynamics simulation with weak coupling to heat and material baths

Eslami, Hossein; Mojahedi, Fatemeh; Moghadasi, Jalil

doi:10.1063/1.3474951

Cited by 53 publications

(45 citation statements)

References 43 publications

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“…Finally, the generated output files from CHARMM-GUI were used for the next MD simulation step using GROMACS. Initially, the energy of the system was minimized using steepest descent method, followed by equilibration at room temperature of 300 K and 1 bar pressure, with the Berendsen weak coupling method to regulate the temperature and pressure of the system 77 . Finally, MD simulation production run was carried out for 50 ns to check the stability of the protein alone and in complex with the ligands.…”

Section: Methodsmentioning

confidence: 99%

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Syed

Arya

et al. 2017

Sci Rep

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P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7-dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog – Pip1 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) – is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer.

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Section: Methodsmentioning

confidence: 99%

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Syed

Arya

et al. 2017

Sci Rep

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“…Finally 85 ns MD simulation for equilibration and production was carried out for the system with 3D periodic boundary in NPT ensemble imposed. Weak coupling methods [44] were applied with coupling constants of 0.1 ps and 0.5 ps respectively to maintain the systems at 298 K and 1 Bar. Bonds involving hydrogen were constained with LINCS algorithm for protein and SETTLE algorithm for water [45,46], thus permitted using a integrate step of 2 fs.…”

Section: Methodsmentioning

confidence: 99%

Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor

Chu

Ding²,

Chu³

et al. 2014

BMC Complement Altern Med

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BackgroundBerberine is an isoquinoline alkaloid mainly extracted from Rhizoma Coptidis and has been shown to possess a potent inhibitory activity against bacterial. However, the role of berberine in anti-bacterial action has not been extensively studied.MethodsThe animal model was established to investigate the effects of berberine on bacterial and LPS infection. Docking analysis, Molecular dynamics simulations and Real-time RT-PCR analysis was adopted to investigate the molecular mechanism.ResultsTreatment with 40 mg/kg berberine significantly increased the survival rate of mice challenged with Salmonella typhimurium (LT2), but berberine show no effects in bacteriostasis. Further study indicated that treatment with 0.20 g/kg berberine markedly increased the survival rate of mice challenged with 2 EU/ml bacterial endotoxin (LPS) and postpone the death time of the dead mice. Moreover, pretreatment with 0.05 g/kg berberine significantly lower the increasing temperature of rabbits challenged with LPS. The studies of molecular mechanism demonstrated that Berberine was able to bind to the TLR4/MD-2 receptor, and presented higher affinity in comparison with LPS. Furthermore, berberine could significantly suppressed the increasing expression of NF-κB, IL-6, TNFα, and IFNβ in the RAW264.7 challenged with LPS.ConclusionBerberine can act as a LPS antagonist and block the LPS/TLR4 signaling from the sourse, resulting in the anti-bacterial action.

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“…The ‘Standard Dynamics Cascade’ Protocol [21] of DS 2.5 was implemented with a time step of 1 fs. The initial minimization of the implicitly solvated protein–ligand complex was carried out in two steps on residues of a selected sphere of a 13 Å radius inscribing the ligand, binding site and its surrounding residues and loops, keeping about two thirds of the protein domain fixed throughout the whole dynamics simulation cascade.…”

Section: Materials and Methodologymentioning

confidence: 99%

New inhibitors of VEGFR-2 targeting the extracellular domain dimerization process

ElGamacy¹,

Shalaby²,

Elkodsh³

et al. 2011

Bioinformation

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We are reporting the discovery of small molecule inhibitors for vascular endothelial growth factor receptor type 2 (VEGFR-2) extracellular domain. The VEGFR-2 extracellular domain is responsible for the homo-dimerization process, which has been recently reported as a main step in VEGFR signal transduction cascade. This cascade is essential for the vascularization and survival of most types of cancers. Two main design strategies were used; Molecular docking-based Virtual Screening and Fragment Based Design (FBD). A virtual library of drug like compounds was screened using a cascade of docking techniques in order to discover an inhibitor that binds to this new binding site. Rapid docking methodology was used first to filter the large number of compounds followed by more accurate and slow ones. Fragment based molecular design was adopted afterwards due to unsatisfactory results of screening process. Screening and design process resulted in a group of inhibitors with superior binding energies exceeding that of the natural substrate. Molecular dynamics simulation was used to test the stability of binding of these inhibitors and finally the drug ability of these compounds was assisted using Lipinski rule of five. By this way the designed compounds have shown to possess high pharmacologic potential as novel anticancer agents.

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Molecular dynamics simulation with weak coupling to heat and material baths

Cited by 53 publications

References 43 publications

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor

New inhibitors of VEGFR-2 targeting the extracellular domain dimerization process

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