17β-estradiol (E2) in membranes: Orientation and dynamic properties

Guo, Jason; Yang, De‐Ping; Tian, Xiaoyu; Vemuri, V. Kiran; Yin, Daqiang; Li, Chen; Duclos, R.; Shen, Litao; Ma, Xiaoyu; Janero, David R.; Makriyannis, Alexandros

doi:10.1016/j.bbamem.2015.11.015

Cited by 9 publications

(6 citation statements)

References 44 publications

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“…Hence, ligand–membrane MD simulations could provide an attractive, additional, and possibly alternative way of screening for potentially active ligand candidates targeted to membrane-associated proteins with more rigor than only docking calculations but using less computational resources than extensive MD simulation. This is supported by previous studies focused on the effects of membrane orientation for various drug molecules, − and regarding ligands targeted to the membrane-bound catechol- O -methyltransferase, MD simulations changed the drug design paradigm …”

Section: Introductionmentioning

confidence: 52%

Expanding the Paradigm of Structure-Based Drug Design: Molecular Dynamics Simulations Support the Development of New Pyridine-Based Protein Kinase C-Targeted Agonists

et al. 2023

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Protein kinase C (PKC) modulators hold therapeutic potential for various diseases, including cancer, heart failure, and Alzheimer’s disease. Targeting the C1 domain of PKC represents a promising strategy; the available protein structures warrant the design of PKC-targeted ligands via a structure-based approach. However, the PKC C1 domain penetrates the lipid membrane during binding, complicating the design of drug candidates. The standard docking–scoring approach for PKC lacks information regarding the dynamics and the membrane environment. Molecular dynamics (MD) simulations with PKC, ligands, and membranes have been used to address these shortcomings. Previously, we observed that less computationally intensive simulations of just ligand–membrane interactions may help elucidate C1 domain-binding prospects. Here, we present the design, synthesis, and biological evaluation of new pyridine-based PKC agonists implementing an enhanced workflow with ligand–membrane MD simulations. This workflow holds promise to expand the approach in drug design for ligands targeted to weakly membrane-associated proteins.

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Section: Introductionmentioning

confidence: 52%

Expanding the Paradigm of Structure-Based Drug Design: Molecular Dynamics Simulations Support the Development of New Pyridine-Based Protein Kinase C-Targeted Agonists

et al. 2023

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“…1% E2@PCL/SF and 0.1% E2@PCL/SF showed a similar E2 release profile which was higher than 5% E2@PCL/SF. Steroid molecules such as E2 and estrone are known to form noncovalent interactions such as hydrogen bond with polymers containing polar side groups such as −CO. , Polar −CO side groups are present in PCL. Moreover, natural polymer SF is rich in polar side groups which can participate in H-bonding with estradiol.…”

Section: Results and Discussionmentioning

confidence: 99%

Estradiol-Loaded Poly(ε-caprolactone)/Silk Fibroin Electrospun Microfibers Decrease Osteoclast Activity and Retain Osteoblast Function

Steffi

Wang

Kong

et al. 2018

ACS Appl. Mater. Interfaces

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Estrogen, a steroid hormone, plays an important role in modulating osteoclast proliferation and development. Estrogen deficiency boosts osteoclast activity, leading to osteoporosis in elderly women. In this study, 17-ß estradiol (E2)-loaded poly(ε-caprolactone) (PCL)/silk fibroin (SF) electrospun microfibers were developed as a proposed localized E2 delivery system to treat osteoporotic fractures. PCL is a synthetic polymer known for its biocompatibility and excellent mechanical properties. The bioactivity of PCL was enhanced by mixing it with a natural SF polymer that has low immunogenicity and inherent bioactivity. Different ratios of PCL/SF blends were electrospun and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and water contact angle measurement. PCL and SF at a ratio of 50:50 (PCL50/SF50) augmented cell proliferation of murine preosteoblast MC3T3-E1 cells and murine preosteoclast RAW 264.7 cells. Hence, PCL50/SF50 was selected and mixed with three concentrations of E2 to produce electrospun fiber mesh (0.1% E2@PCL/SF, 1% E2@PCL/SF, and 5% E2@PCL/SF). Sustained release of E2 was obtained for about 3 weeks at higher E2 concentration 5% E2@PCL/SF. An E2-loaded PCL50/SF50 elecrospun microfiber (1% E2@PCL/SF and 5% E2@PCL/SF) reduced tartrate-resistant acid phosphate activity, total DNA, and multinucleated cell formation of osteoclasts. On the other hand, the alkaline phosphatase activity and collagen I expression of osteoblasts were retained on all E2-loaded electrospun microfibers. The E2@PCL/SF system shows potential to be used for localized E2 delivery for the treatment of osteoporotic fractures.

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“…Combining MD and QM enables further research into E2 membrane crossing. It provides information not only about the E2 orientation in the membrane (MD) but also about the strength of the electrostatic potential mapped on the electron density surface (QM) [ 135 ]. These data, derived from a HDL disc model, enable deeper insight into the mechanism of E2 incorporation into lipid membranes and is an important step forward to develop tissue-specific discs encircled by a membrane, which would serve as transporters for E2 or its derivatives.…”

Section: Application Of Molecular Modelling Methods In the Study Omentioning

confidence: 99%

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

Mazurek

Szeleszczuk

Simonson

et al. 2020

IJMS

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In this review, applications of various molecular modelling methods in the study of estrogens and xenoestrogens are summarized. Selected biomolecules that are the most commonly chosen as molecular modelling objects in this field are presented. In most of the reviewed works, ligand docking using solely force field methods was performed, employing various molecular targets involved in metabolism and action of estrogens. Other molecular modelling methods such as molecular dynamics and combined quantum mechanics with molecular mechanics have also been successfully used to predict the properties of estrogens and xenoestrogens. Among published works, a great number also focused on the application of different types of quantitative structure–activity relationship (QSAR) analyses to examine estrogen’s structures and activities. Although the interactions between estrogens and xenoestrogens with various proteins are the most commonly studied, other aspects such as penetration of estrogens through lipid bilayers or their ability to adsorb on different materials are also explored using theoretical calculations. Apart from molecular mechanics and statistical methods, quantum mechanics calculations are also employed in the studies of estrogens and xenoestrogens. Their applications include computation of spectroscopic properties, both vibrational and Nuclear Magnetic Resonance (NMR), and also in quantum molecular dynamics simulations and crystal structure prediction. The main aim of this review is to present the great potential and versatility of various molecular modelling methods in the studies on estrogens and xenoestrogens.

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17β-estradiol (E2) in membranes: Orientation and dynamic properties

Cited by 9 publications

References 44 publications

Expanding the Paradigm of Structure-Based Drug Design: Molecular Dynamics Simulations Support the Development of New Pyridine-Based Protein Kinase C-Targeted Agonists

Expanding the Paradigm of Structure-Based Drug Design: Molecular Dynamics Simulations Support the Development of New Pyridine-Based Protein Kinase C-Targeted Agonists

Estradiol-Loaded Poly(ε-caprolactone)/Silk Fibroin Electrospun Microfibers Decrease Osteoclast Activity and Retain Osteoblast Function

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

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