scholarly journals Molecular Docking and Molecular Dynamics Studies on Selective Synthesis of α-Amyrin and β-Amyrin by Oxidosqualene Cyclases from Ilex Asprella

2019 ◽  
Vol 20 (14) ◽  
pp. 3469 ◽  
Author(s):  
Zhixue Wu ◽  
Hui Xu ◽  
Meiling Wang ◽  
Ruoting Zhan ◽  
Weiwen Chen ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Protein Structures ◽  
Free Energy Calculations ◽  
Selective Synthesis ◽  
Total Production ◽  
Oxidosqualene Cyclases ◽  
Free Energy Decomposition

Amyrins are the immediate precursors of many pharmaceutically important pentacyclic triterpenoids. Although various amyrin synthases have been identified, little is known about the relationship between protein structures and the constituent and content of the products. IaAS1 and IaAS2 identified from Ilex asprella in our previous work belong to multifunctional oxidosqualene cyclases and can produce α-amyrin and β-amyrin at different ratios. More than 80% of total production of IaAS1 is α-amyrin; while IaAS2 mainly produces β-amyrin with a yield of 95%. Here, we present a molecular modeling approach to explore the underlying mechanism for selective synthesis. The structures of IaAS1 and IaAS2 were constructed by homology modeling, and were evaluated by Ramachandran Plot and Verify 3D program. The enzyme-product conformations generated by molecular docking indicated that ASP484 residue plays an important role in the catalytic process; and TRP611 residue of IaAS2 had interaction with β-amyrin through π–σ interaction. MM/GBSA binding free energy calculations and free energy decomposition after 50 ns molecular dynamics simulations were performed. The binding affinity between the main product and corresponding enzyme was higher than that of the by-product. Conserved amino acid residues such as TRP257; TYR259; PHE47; TRP534; TRP612; and TYR728 for IaAS1 (TRP257; TYR259; PHE473; TRP533; TRP611; and TYR727 for IaAS2) had strong interactions with both products. GLN450 and LYS372 had negative contribution to binding affinity between α-amyrin or β-amyrin and IaAS1. LYS372 and ARG261 had strong repulsive effects for the binding of α-amyrin with IaAS2. The importance of Lys372 and TRP612 of IaAS1, and Lys372 and TRP611 of IaAS2, for synthesizing amyrins were confirmed by site-directed mutagenesis. The different patterns of residue–product interactions is the cause for the difference in the yields of two products.

scholarly journals DFT Calculation, Molecular Docking and Molecular Dynamics Simulation Study on Substituted Phenylacetamide and Benzohydrazide Derivatives

2021 ◽  
Author(s):  
Vidyasrilekha Yele ◽  
Dilep Kumar Sigalapalli ◽  
Srikanth Jupudi ◽  
Mohammed Afzal Azam
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Molecular Surface ◽  
Basis Set ◽  
Nucleophilic Attack

Abstract The atomic and molecular properties of the title compounds were calculated by Jaguar using a basis set B3LYP/6-31G**++ with hybrid DFT in the gas phase, to determine the chemical reactivity. Analysis of Quantum chemical features such as HOMO and LUMO explained that the electronic charge transfer occurred within the system through conjugated paths of the selected compounds. The nucleophilic and electrophilic reactive sites are recognized from the molecular electrostatic potential plot. Electrophilic and nucleophilic attack-prone molecular sites were predicted by mapping ALIE and ALEA values to the molecular surface. The bond dissociation energy of the high active compound 15 (2-chloro-N-(2-(2-(2-(2-chlorobenzoyl)hydrazineyl)-2-oxoethoxy)phenyl)acetamide) was calculated to assess the probability of compounds autoxidation or degradation. Further, molecular docking, binding free energy calculations, and ADMET profile of the degradation products (DPs) of compound 15 was carried out to determine the binding affinity and toxicity profile of the formed DPs compared with the parent compound. A 150 ns molecular dynamics (MD) simulation was performed to evaluate the binding stability of the compound 15/4URL complex using Desmond. Binding free energy and binding affinity of the complex were computed for 100 trajectory frames using the MM-GBSA approach.

scholarly journals Binding Affinities of Sanggenon Derivatives as PTP1B Inhibitors; Using Molecular Dynamics and Free Energy Calculations

2021 ◽  
Author(s):  
Safak OZHAN KOCAKAYA
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Tyrosine Phosphatase ◽  
Decomposition Analysis ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Energy Decomposition Analysis ◽  
Free Energy Decomposition ◽  
Poisson Boltzmann ◽  
Ptp1b Inhibitors

Abstract Recently, protein tyrosine phosphatase 1B (PTP1B) inhibitors have become the frontier as possible targeting for anti-cancer and antidiabetic drugs. The contemporary observe represents a pc assisted version to investigate the importance of precise residues within the binding web site of PTP1B with numerous Sanggenon derivatives remoted from nature. Molecular dynamics (MD) simulations were performed to estimate the dynamics of the complexes, and absolute binding unfastened energies have been calculated with exclusive additives, and carried out through the usage of the Molecular Mechanics-Poisson-Boltzmann floor region (MM-PB/SA) and Generalized Born surface vicinity (MM-GB/SA) strategies. The effects show that the expected free energies of the complexes are normally constant with the available experimental statistics. MM/GBSA free energy decomposition analysis shows that the residues Asp29, Arg24, Met258, and , Arg254 in the second active site in PTP1B are crucial for the excessive selectivity of the inhibitors.

scholarly journals Computational Investigations on Interactions Between DNA and Flavonols

2021 ◽  
Vol 12 (6) ◽  
pp. 8117-8127
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Side Effects ◽  
Free Energy Calculations ◽  
Main Task ◽  
Computational Results ◽  
Ligand Complex ◽  
Drug Designing

Today, the main task of researchers is to study and develop drugs that are less toxic and have lesser side effects. The principal motive of this research is to study and analyze the interaction between naturally active compounds flavonoids with biomolecule DNA. Since the interaction between DNA and ligand is essential in drug designing, this study will provide a good base for further research and development of less toxic and more efficient drugs for various diseases. The selected compounds for this study are Kaempferide, Kaempferol, Morin, and Rutin. They all fall into the category ‘flavonols’ of flavonoids. Computational methods are implemented for theoretical drug designing. These are molecular optimization, molecular docking, and molecular dynamics. Computational results are compared with experimental data from previous studies. Molecular docking gives the most preferred orientation of ligands within DNA, and Molecular Dynamics provides the details about the DNA-ligand complex with respect to time. Free energy calculations were also performed by implementing MMPBSA and MMGBSA calculations.

scholarly journals Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations

2017 ◽  
Vol 13 (4) ◽  
pp. 736-749 ◽  
Author(s):  
Huiming Cao ◽  
Yuzhen Sun ◽  
Ling Wang ◽  
Chunyan Zhao ◽  
Jianjie Fu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Polybrominated Diphenyl Ethers ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Binding Mechanism ◽  
Diphenyl Ethers ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

The binding of TTR with sulfated-PBDEs and OH-PBDEs shows different molecular recognition mechanisms.

scholarly journals Identification of the Potential Hits for Hindering Interaction of SARS-CoV-2 Main Protease (M pro ) from the Pool of Antiviral Phytochemicals utilizing Molecular Docking and Molecular Dynamics (MD) Simulations

2021 ◽  
Author(s):  
Chirag N. Patel ◽  
Dharmesh G. Jaiswal ◽  
Siddhi P. Jani ◽  
Naman Mangukia ◽  
Robin M. Parmar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Virus Assembly ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Host Protein ◽  
Dynamic Simulations ◽  
Main Protease

Abstract The novel SARS-CoV-2 is an etiological factor that triggers Coronavirus disease in 2019 (COVID-19) and tends to be an imminent occurrence of a pandemic. Out of all recognized solved complexes linked to SARS-CoV, Main protease (Mpro) is considered a desirable antiviral phytochemical that play a crucial role in virus assembly and possibly non-interactive capacity to adhere to any viral host protein. In this research, SARS-CoV-2 MPro was chosen as a focus for the detection of possible inhibitors using a variety of different analytical methods such as molecular docking, ADMET analysis, dynamic simulations and binding free energy measurements. Virtual screening of known natural compounds recognized Withanoside V, Withanoside VI, Racemoside B, Racemoside A and Shatavarin IX as future inhibitors of SARS-CoV-2 MPro with stronger energy binding. Also, simulations of molecular dynamics for a 100 ns time scale showed that much of the main SARS-CoV-2 MPro interactions had been maintained in the simulation routes. Binding free energy calculations using the MM/PBSA method ranked the top five possible natural compounds that can act as effective SARS-CoV-2 MPro inhibitors.

scholarly journals Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

2020 ◽  
Author(s):  
Dr. Chirag N. Patel ◽  
Dr. Prasanth Kumar S. ◽  
Dr. Himanshu A. Pandya ◽  
Dr. Rakesh M. Rawal
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculations ◽  
Dynamics Simulations

<p>The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.</p>

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