MD simulations of estrogen receptors (ER) and docking analysis of DPN analogues reveal insights about subtype-receptor selectivity

2019 ◽  
Vol 08 ◽  
Author(s):  
Marlet Martinez
Keyword(s):  
Estrogen Receptors ◽  
Md Simulations ◽  
Docking Analysis ◽  
Receptor Selectivity

scholarly journals Identification of PRMT5 Inhibitors with Novel Scaffold Structures through Virtual Screening and Biological Evaluations

2021 ◽  
Author(s):  
Lun Zhang ◽  
Chenxi Cao ◽  
Jia Jin ◽  
Yaohua Fan ◽  
Xiaoguang Wang ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Md Simulations ◽  
Leukemia Cells ◽  
Moderate Activity ◽  
Arginine Methyltransferase ◽  
Docking Analysis ◽  
Cycle Arrest ◽  
Anticancer Target ◽  
Novel Scaffold ◽  
Molecular Docking Analysis

Abstract Protein arginine methyltransferase 5 (PRMT5), an important member in PRMT family, has been validated as a promising anticancer target. In this study, through the combination of virtual screening and biological experiments, we have identified two PRMT5 inhibitors with novel scaffold structures. Among them, compound Y2431 showed moderate activity with IC50 value of 10.09 μM and displayed good selectivity against other methyltransferases. The molecular docking analysis and molecular dynamics (MD) simulations suggested that the compound occupied the substrate-arginine binding site. Furthermore, Y2431 exhibited anti-proliferative activity to leukemia cells by inducing cell cycle arrest. Overall, the hit compound could provide a novel scaffold for further optimization of small-molecule PRMT5 inhibitors.

Computational Study of the Binding Modes of Diverse DPN Analogues on Estrogen Receptors (ER) and the Biological Evaluation of a New Potential Antiestrogenic Ligand

2019 ◽  
Vol 18 (11) ◽  
pp. 1508-1520 ◽  
Author(s):  
M. Martinez-Archundia ◽  
J.B. García-Vázquez ◽  
B. Colin-Astudillo ◽  
M. Bello ◽  
B. Prestegui-Martel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptors ◽  
Computational Study ◽  
Sequence Similarity ◽  
Critical Role ◽  
Biological Evaluation ◽  
New Drugs ◽  
Docking Analysis ◽  
Biological Studies ◽  
In Silico Admet

Estrogen (17β-estradiol) is essential for normal growth and differentiation in the mammary gland. In the last three decades, previous investigations have revealed that Estrogen Receptor Alpha (ERα) plays a critical role in breast cancer. More recently, observations regarding the widespread expression of ERβ-like proteins in normal and neoplastic mammary tissues have suggested that ERβ is also involved in the mentioned pathology. Design of new drugs both steroidal and nonsteroidal that target any of these receptors represents a promise to treat breast cancer although it remains a challenge due to the sequence similarity between their catalytic domains. In this work, we propose a new set of compounds that could effectively target the estrogen receptors ERα and ERβ. These ligands were designed based on the chemical structure of the ERβ-selective agonist Diarylpropionitrile (DPN). The designed ligands were submitted to in silico ADMET studies, yielding in a filtered list of ligands that showed better drug-like properties. Molecular dynamics simulations of both estrogen receptors and docking analysis were carried-out employing the designed compounds, from which two were chosen due to their promising characteristics retrieved from theoretical results (docking analysis or targeting receptor predictions). They were chemically synthetized and during the process, two precursor ligands were also obtained. These four ligands were subjected to biological studies from which it could be detected that compound mol60b dislplayed inhibito

scholarly journals Estrogenic Effect of Scoparia dulcis (Linn) Extract in Mice Uterus and In Silico Molecular Docking Studies of Certain Compounds with Human Estrogen Receptors

2020 ◽  
Author(s):  
Khamhee Wangsa ◽  
Indira Sarma ◽  
Purbajyoti Saikia ◽  
Dhanabalan Ananthakrishnan ◽  
Hirendra Nath Sarma ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Estrogen Receptors ◽  
Binding Affinity ◽  
In Silico ◽  
Md Simulations ◽  
Docking Studies ◽  
Female Reproduction ◽  
Molecular Docking Studies ◽  
Scoparia Dulcis ◽  
In Silico Molecular Docking

Background: Scoparia dulcis Linn. is reported to be used by women of Assam and Arunachal Pradesh in northeast India for treating menstrual disorders. Scoparia dulcis contains compounds that bind with estrogen receptors (ERα and ERβ) evidenced by increased PCNA in endometrial epithelium. Methods: Crude extract was orally administered at the dose of 500 mg/kg body weight/day to the female mice (60–70 days old) in five different groups. Each group containing six females included: (I) cyclic control, (II) cyclic extract treated, (III) Ovariectomized (OVX)-vehicle treated (Control), (IV) OVX-E2 treated (V) OVX- extract treated. Extract was administered for eight days to the cyclic groups and three days to the OVX groups. PCNA was detected immunohistochemically in uterine tiss ues and signals were analyzed by Image J software (NIH, USA). Compounds were separated by GC-MS and identified using NIST. In silico molecular docking studies was performed with human estrogen receptors (ERα and ERβ). Molecular dynamics (MD) simulations of the best interacting compound was done using gromacs. Results: The results showed cell proliferation in the uterine endometrium evidenced by PCNA. Two phytocompounds, Octadecanoic acid and methyl stearate showed binding affinity with ERα and ERβ. Conclusion: Scoparia dulcis contains compounds having binding affinity with ERα and ERβ. The present study is the first report on compounds from Scoparia dulcis showing binding affinity with human estrogen receptors which may have biological effect on female reproduction.

Computational investigation of zerumbone as an inhibitor of TNF-alpha using molecular dynamics and molecular docking methods

2020 ◽  
Vol 17 ◽  
Author(s):  
Salam Pradeep Singh ◽  
Khumukcham Nongalleima ◽  
Ningthoujam Indrajit Singh ◽  
Wahengbam Kabita Chanu ◽  
Thiyam Ramsing Singh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Cell ◽  
Md Simulations ◽  
Inhibitory Effect ◽  
Computational Techniques ◽  
Computational Investigation ◽  
Docking Analysis ◽  
Tnf Α ◽  
Anti Cancer ◽  
Cancer Activity

Background: There are several reports on the anti-cancer property zerumbone such as breast, cervical and ovarian cancer. But the investigation on the actual protein target is the least concern and there are few reports on the inhibitory effect of zerumbone against specific cancer-causing proteins and enzymes. Therefore, investigation is required in a much deeper molecular level. Objective: To determine the anti-proliferative activity of Zerumbone against cervical cancer cell and assessing its TNF-α enzyme inhibitory action. Methods: The investigation emphasized anti-cancer activity of zerumbone against HeLa cells on and its subsequent TNF-α assay. Further, computational studies of Zerumbone as an inhibitor of TNF-α were carried out using computational techniques such as docking and MD simulations. Results and Discussion: From the molecular docking analysis, it was observed and substantiated that the α,β-Unsaturated carbonyl scaffold is the main driving force for its anti-cancer activity in zerumbone and inhibition of TNF-α. Conclusion: Zerumbone might be potent anti-cancer agents targeting the HeLa cancer cell lines and inhibiting the TNF-α enzyme.

scholarly journals The Influence of Calcium toward Order/Disorder Conformation of Repeat-in-Toxin (RTX) Structure of Family I.3 Lipase from Pseudomonas fluorescens AMS8

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 579
Author(s):  
Nur Shidaa Mohd Ali ◽  
Abu Bakar Salleh ◽  
Thean Chor Leow ◽  
Raja Noor Zaliha Raja Abd Rahman ◽  
Mohd Shukuri Mohamad Ali
Keyword(s):  
Calcium Binding ◽  
Metal Ion ◽  
Md Simulation ◽  
Structural Changes ◽  
Decisive Role ◽  
Md Simulations ◽  
High Binding Energy ◽  
Docking Analysis ◽  
Repeat Structure ◽  
Functional Dynamics

Calcium-binding plays a decisive role in the folding and stabilization of many RTX proteins, especially for the RTX domain. Although many studies have been conducted to prove the contribution of Ca2+ ion toward the folding and stabilization of RTX proteins, its functional dynamics and conformational structural changes remain elusive. Here, molecular docking and molecular dynamics (MD) simulations were performed to analyze the contribution of Ca2+ ion toward the folding and stabilization of the RTX lipase (AMS8 lipase) structure. AMS8 lipase contains six Ca2+ ions (Ca1–Ca6). Three Ca2+ ions (Ca3, Ca4, and Ca5) were bound to the RTX parallel β-roll motif repeat structure (RTX domain). The metal ion (Ca2+) docking analysis gives a high binding energy, especially for Ca4 and Ca5 which are tightly bound to the RTX domain. The function of each Ca2+ ion is further analyzed using the MD simulation. The removal of Ca3, Ca4, and Ca5 caused the AMS8 lipase structure to become unstable and unfolded. The results suggested that Ca3, Ca4, and Ca5 stabilized the RTX domain. In conclusion, Ca3, Ca4, and Ca5 play a crucial role in the folding and stabilization of the RTX domain, which sustain the integrity of the overall AMS8 lipase structure.

scholarly journals Glycosidic vs. Aglycol Form of Natural Products as Putative Tyrosinase Inhibitors

Biophysica ◽  
2021 ◽  
Vol 1 (4) ◽  
pp. 458-473
Author(s):  
Maria Evgenia Politi ◽  
Kostas Bethanis ◽  
Trias Thireou ◽  
Elias Christoforides
Keyword(s):  
Natural Products ◽  
Md Simulations ◽  
Oxidation Activity ◽  
Docking Analysis ◽  
Naturally Occurring ◽  
Zinc Database ◽  
Tyrosinase Inhibitors ◽  
Inhibitory Molecules ◽  
Natural Inhibitors

Numerous natural products and designed molecules have been evaluated as tyrosinase inhibitors that impede enzymes’ oxidation activity. In the present study, new potent natural inhibitors were retrieved from the ZINC database by the similarity-screening of 37 previously reported tyrosinase inhibitors. The screening resulted in 42 candidate inhibitory molecules that were categorized into five groups. Molecular-docking analysis for these compounds, as well as for three others known for their inhibition activity (caffeic acid, naringenin, and gallic acid), was carried out against the tyrosinase structure from Agaricus bisporus (AbTYR). The top-scoring compounds were used for further comparative analysis with their corresponding naturally occurring glycosides. The results suggested that the glycosylated inhibitors could interact better with the enzyme than their aglycon forms. In order to further examine the role of the sugar side group of potent tyrosinase inhibitors, the dynamic behavior of two such pairs of glycosidic/aglycol forms (naringin–naringenin and icariin–icaritin) in their complexes with the enzyme were studied by means of 20-ns MD simulations. The increased number of intermolecular hydrogen bonds and their augmented lifetime between AbTYR and the glycosidic analogues showed that the naringin and icariin molecules form more stable complexes than naringenin and icaritin with tyrosinase, and thus are more potent inhibitors.

Efficient Treatment of Fixed and Induced Dipolar Interactions

2000 ◽  
Vol 653 ◽  
Author(s):  
Celeste Sagui ◽  
Thoma Darden
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Lagrangian Formalism ◽  
Dipolar Interactions ◽  
Time Step ◽  
Efficient Treatment ◽  
Particle Mesh Ewald ◽  
Fixed Charges ◽  
Self Consistency ◽  
Induced Dipoles

AbstractFixed and induced point dipoles have been implemented in the Ewald and Particle-Mesh Ewald (PME) formalisms. During molecular dynamics (MD) the induced dipoles can be propagated along with the atomic positions either by interation to self-consistency at each time step, or by a Car-Parrinello (CP) technique using an extended Lagrangian formalism. The use of PME for electrostatics of fixed charges and induced dipoles together with a CP treatment of dipole propagation in MD simulations leads to a cost overhead of only 33% above that of MD simulations using standard PME with fixed charges, allowing the study of polarizability in largemacromolecular systems.

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