scholarly journals Use of Molecular Dynamics for the Refinement of an Electrostatic Model for the In Silico Design of a Polymer Antidote for the Anticoagulant Fondaparinux

2013 ◽  
Vol 2013 ◽  
pp. 1-11
Author(s):  
Adriana Cajiao ◽  
Ezra Kwok ◽  
Bhushan Gopaluni ◽  
Jayachandran N. Kizhakkedathu
Keyword(s):  
Molecular Dynamics ◽  
In Silico ◽  
Md Simulations ◽  
Polymer Structure ◽  
Quantitative Model ◽  
Electrostatic Model ◽  
Association Rate ◽  
Model Predictions ◽  
Daunting Challenge ◽  
Association Rate Constants

Molecular dynamics (MD) simulations results are herein incorporated into an electrostatic model used to determine the structure of an effective polymer-based antidote to the anticoagulant fondaparinux. In silico data for the polymer or its cationic binding groups has not, up to now, been available, and experimental data on the structure of the polymer-fondaparinux complex is extremely limited. Consequently, the task of optimizing the polymer structure is a daunting challenge. MD simulations provided a means to gain microscopic information on the interactions of the binding groups and fondaparinux that would have otherwise been inaccessible. This was used to refine the electrostatic model and improve the quantitative model predictions of binding affinity. Once refined, the model provided guidelines to improve electrostatic forces between candidate polymers and fondaparinux in order to increase association rate constants.

scholarly journals In Silico Exploration of Efficacious Inhibitors for SARS-CoV-2’s Papain-like Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
Wendy Cornell ◽  
Binquan Luan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanism ◽  
In Silico ◽  
Rank Order ◽  
Md Simulations ◽  
Flexible Docking ◽  
Docking Method ◽  
Approved Drugs ◽  
Fda Approved Drugs

We applied the flexible docking method to rank-order all FDA-approved drugs as inhibitors for the papain-like protease (PLpro) of SRAS-CoV-2. We also evaluated these results using molecular dynamics (MD) simulations. From MD simulations, we unveiled the molecular mechanism for a known inhibitor rac5c's binding with PLpro. <br>

scholarly journals Inactivation and reactivation of ribonuclease A studied by computer simulation

Open Biology ◽  
2012 ◽  
Vol 2 (7) ◽  
pp. 120088 ◽  
Author(s):  
Gavin M. Seddon ◽  
Robert P. Bywater
Keyword(s):  
Molecular Dynamics ◽  
Computer Simulation ◽  
In Silico ◽  
Tertiary Structure ◽  
Md Simulations ◽  
Globular Proteins ◽  
Ribonuclease A ◽  
Amino Acid Residues ◽  
Constituent Amino Acid ◽  
Single Protein

The year 2011 marked the half-centenary of the publication of what came to be known as the Anfinsen postulate, that the tertiary structure of a folded protein is prescribed fully by the sequence of its constituent amino acid residues. This postulate has become established as a credo , and, indeed, no contradictions seem to have been found to date. However, the experiments that led to this postulate were conducted on only a single protein, bovine ribonuclease A (RNAse). We conduct molecular dynamics (MD) simulations on this protein with the aim of mimicking this experiment as well as making the methodology available for use with basically any protein. There have been many attempts to model denaturation and refolding processes of globular proteins in silico using MD, but only a few examples where disulphide-bond containing proteins were studied. We took the view that if the reductive deactivation and oxidative reactivation processes of RNAse could be modelled in silico, this would provide valuable insights into the workings of the classical Anfinsen experiment.

scholarly journals In Silico Exploration of Efficacious Inhibitors for SARS-CoV-2’s Papain-like Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
Wendy Cornell ◽  
Binquan Luan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanism ◽  
In Silico ◽  
Rank Order ◽  
Md Simulations ◽  
Flexible Docking ◽  
Docking Method ◽  
Approved Drugs ◽  
Fda Approved Drugs

We applied the flexible docking method to rank-order all FDA-approved drugs as inhibitors for the papain-like protease (PLpro) of SRAS-CoV-2. We also evaluated these results using molecular dynamics (MD) simulations. From MD simulations, we unveiled the molecular mechanism for a known inhibitor rac5c's binding with PLpro. <br>

Recent Advances in the In-silico Structure-based and Ligand-based Approaches for the Design and Discovery of Agonists and Antagonists of A2A Adenosine Receptor

2019 ◽  
Vol 25 (7) ◽  
pp. 774-782 ◽  
Author(s):  
Nikhil Agrawal ◽  
Balakumar Chandrasekaran ◽  
Amal Al-Aboudi
Keyword(s):  
Molecular Dynamics ◽  
Membrane Protein ◽  
In Silico ◽  
Recent Progress ◽  
Md Simulations ◽  
Pharmacophore Modeling ◽  
A2a Adenosine Receptor ◽  
A2a Receptor ◽  
In Silico Studies ◽  
The Family

A2A receptor belongs to the family of GPCRs, which are the most abundant membrane protein family. Studies in the last few decades have shown the therapeutic applications of A2A receptor in various diseases. In the present mini-review, we have discussed the recent progress in the in-silico studies of the A2A receptor. Herein, we described the different structures of A2A receptor, the discovery of new agonists and antagonists using virtualscreening/ docking, pharmacophore modeling, and QSAR based pharmacophore modeling. We have also discussed various molecular dynamics (MD) simulations studies of A2A receptor in complex with ligands.

scholarly journals Spectroscopic and In Silico Studies on the Interaction of Substituted Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one Derivatives with c-Myc G4-DNA

2021 ◽  
Vol 22 (11) ◽  
pp. 6028
Author(s):  
Simone Mulliri ◽  
Aatto Laaksonen ◽  
Pietro Spanu ◽  
Riccardo Farris ◽  
Matteo Farci ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
In Silico ◽  
Water Solution ◽  
Md Simulations ◽  
Anticancer Activities ◽  
Myc Oncogene ◽  
G4 Dna ◽  
In Silico Studies ◽  
Wide Range ◽  
Dynamics Simulations

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2–4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery.

scholarly journals In Silico Screening and Analysis of Potential Inhibitors of Arylamine N-Acetyltransferases (NATs) from the Traditional Chinese Medicine: A Study Using Free Available Tools

2017 ◽  
Author(s):  
Francisco Azevedo ◽  
Joveline Richardt ◽  
Mayrla Oliveira ◽  
Inês Araujo ◽  
Ricardo Oliveira ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
In Silico ◽  
Md Simulations ◽  
Quality Information ◽  
Pharmacological Properties ◽  
Endogenous Compounds ◽  
Potential Inhibitors ◽  
Specific Ligand

Arylamine N-acetyltransferases (NATs) are cytosolic enzymes, highly polymorphic, present in both eukaryotes and prokaryotes. These enzymes play an important role in the detoxification and activation of xenobiotics as well as in the synthesis of endogenous compounds. Specific NATs have been pointed out in the literature as possible therapeutic targets. In particular, the human NAT1, for the treatment of certain cancers, and the NAT from M. tuberculosis (TBNAT), for the treatment of tuberculosis. This paper describes an in silico approach to prospect and select potentially inhibitors of NAT1 and TBNAT from the Traditional Chinese Medicine (TCM) using free available tools. A library with ligands from TCM was previously screened in order to select only compounds with optimal pharmacological properties. The affinity of the selected ligands with respect to NAT enzymes was then evaluated by virtual screening (VS). Subsequently, the complexes with the best ligands were submitted to molecular dynamics (MD) simulations aiming to obtain better quality information on affinity and selectivity. The results for one specific ligand, ZINC14690579, indicated its potential for affinity and selectivity. ZINC14690579 structure may represent the discovery of a new scaffold for future development of NAT inhibitors.

scholarly journals Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Yuwei Wang ◽  
Rui Han ◽  
Huimin Zhang ◽  
Hongli Liu ◽  
Jiazhong Li ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Androgen Receptor ◽  
In Silico ◽  
Binding Free Energy ◽  
Predictive Ability ◽  
Md Simulations ◽  
Qsar Model ◽  
Molecular Structures ◽  
Binding Modes ◽  
Dynamics Simulations

The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR), are the main endocrine therapies for prostate cancer (PCa). But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.

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.

Split the Charge Difference in Two! a Rule of Thumb for Adding Proper Amounts of Ions in MD Simulations

2020 ◽  
Author(s):  
Matías R. Machado ◽  
Sergio Pantano
Keyword(s):  
Molecular Dynamics ◽  
Ionic Strength ◽  
Molecular Simulations ◽  
Md Simulations ◽  
Good Practices ◽  
Rule Of Thumb ◽  
Ionic Concentrations

<p> Despite the relevance of properly setting ionic concentrations in Molecular Dynamics (MD) simulations, methods or practical rules to set ionic strength are scarce and rarely documented. Based on a recently proposed thermodynamics method we provide an accurate rule of thumb to define the electrolytic content in simulation boxes. Extending the use of good practices in setting up MD systems is promptly needed to ensure reproducibility and consistency in molecular simulations.</p>

Sign in / Sign up

Export Citation Format

Share Document