scholarly journals Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 674
Author(s):  
Ziyad Tariq Muhseen ◽  
Alaa R. Hameed ◽  
Halah M. H. Al-Hasani ◽  
Sajjad Ahmad ◽  
Guanglin Li
Keyword(s):  
Free Energy ◽  
Binding Energy ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Natural Compounds ◽  
Rational Drug Design ◽  
Dynamics Simulation ◽  
Antiviral Compounds ◽  
Rational Drug ◽  
Key Residues

SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

Identification of potential CCR5 inhibitors through pharmacophore-based virtual screening, molecular dynamics simulation and binding free energy analysis

2016 ◽  
Vol 12 (11) ◽  
pp. 3396-3406 ◽  
Author(s):  
Juan Wang ◽  
Mao Shu ◽  
Yuanqiang Wang ◽  
Yong Hu ◽  
Yuanliang Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Energy Analysis ◽  
Binding Free Energy ◽  
Rational Drug Design ◽  
Dynamics Simulation ◽  
Rational Drug ◽  
Combined Strategy ◽  
Free Energy Analysis

Employing the combined strategy to identify novel CCR5 inhibitors and provide a basis for rational drug design.

scholarly journals Virtual screening, molecular dynamics and binding energy-MM-PBSA studies of natural compounds to identify potential EcR inhibitors against Bemisia tabaci Gennadius

2021 ◽  
Author(s):  
Harmilan Kaur Mangat ◽  
Manisha Rani ◽  
Rajesh Kumar Pathak ◽  
Inderjit Singh Yadav ◽  
Divya Utreja ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Energy ◽  
Virtual Screening ◽  
Bemisia Tabaci ◽  
Binding Free Energy ◽  
Insect Pest ◽  
Natural Compounds ◽  
Dynamics Simulation ◽  
Economic Losses

Abstract Whitefly (Bemisia tabaci Gennadius) is a hmpteran phyto polyphagous sucking insect pest which is an important pest of cotton that causes economic losses to the crop by reducing its yield and quality. Ecdysteroids like 20-hydroxy ecdysone (20-E), have significant role in larval moulting, development, and reproduction in pterygota insects. Intending to obstruct these fundamental, developmental physiological processes, the receptor of 20-E, the Ecdysone Receptor (BtEcR) of Bemisia tabaci has been targeted. To identify potent inhibitors of BtEcr, 98,072 natural compounds were retrieved from ZINC database. A structure-based virtual screening of these compounds was conducted for their binding to BtEcR and the top two compounds (ZINC08952607 and ZINC04264850) were selected based on minimum binding energy. 50 ns molecular dynamics simulation (MDS) study was then performed for the prediction of dynamics and stability of BtEcR and top-scoring ligand-BtEcR complexes. Besides, g_mmpbsa tool was used to calculate and analyse binding free energy of BtEcR-ligand complexes. The results revealed that ZINC08952607 and ZINC04264850 had binding free energy of −170.156 kJ/mol and −200.349 kJ/mol, respectively. Thus, these ligands can be utilized as lead compounds for the development of environmentally safe insecticides against the whitefly.

scholarly journals Virtual screening, molecular dynamics and binding energy-MM-PBSA studies of natural compounds to identify potential EcR inhibitors against Bemisia tabaci Gennadius

2021 ◽  
Author(s):  
Harmilan Kaur Mangat ◽  
Manisha Rani ◽  
Rajesh Kumar Pathak ◽  
Inderjit Singh Yadav ◽  
Divya Utreja ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Energy ◽  
Virtual Screening ◽  
Bemisia Tabaci ◽  
Binding Free Energy ◽  
Insect Pest ◽  
Natural Compounds ◽  
Dynamics Simulation ◽  
Economic Losses

Abstract Whitefly (Bemisia tabaci Gennadius) is a hmpteran phyto polyphagous sucking insect pest which is an important pest of cotton that causes economic losses to the crop by reducing its yield and quality. Ecdysteroids like 20-hydroxy ecdysone (20-E), have significant role in larval moulting, development, and reproduction in pterygota insects. Intending to obstruct these fundamental, developmental physiological processes, the receptor of 20-E, the Ecdysone Receptor (BtEcR) of Bemisia tabaci has been targeted. To identify potent inhibitors of BtEcr, 98,072 natural compounds were retrieved from ZINC database. A structure-based virtual screening of these compounds was conducted for their binding to BtEcR and the top two compounds (ZINC08952607 and ZINC04264850) were selected based on minimum binding energy. 50 ns molecular dynamics simulation (MDS) study was then performed for the prediction of dynamics and stability of BtEcR and top-scoring ligand-BtEcR complexes. Besides, g_mmpbsa tool was used to calculate and analyse binding free energy of BtEcR-ligand complexes. The results revealed that ZINC08952607 and ZINC04264850 had binding free energy of − 170.156 kJ/mol and − 200.349 kJ/mol, respectively. Thus, these ligands can be utilized as lead compounds for the development of environmentally safe insecticides against the whitefly.

scholarly journals Interaction of Coumarin Phytoestrogens with ERα and ERβ: A Molecular Dynamics Simulation Study

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1165 ◽  
Author(s):  
Ting Wang ◽  
Yunfei Wang ◽  
Xuming Zhuang ◽  
Feng Luan ◽  
Chunyan Zhao ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Human Life ◽  
Simulation Method ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Molecular Dynamics Methods ◽  
17Β Estradiol ◽  
The Stability

Coumarin phytoestrogens, as one of the important classes of phytoestrogens, have been proved to play an important role in various fields of human life. In this study, molecular simulation method including molecular docking and molecular dynamics methods were performed to explore the various effects between four classical coumarin phytoestrogens (coumestrol, 4-methoxycoumestrol, psoralen and isopsoralen), and estrogen receptors (ERα, ERβ), respectively. The calculated results not only proved that the four coumarin phytoestrogens have weaker affinity than 17β-estradiol to both ERα, and ERβ, but also pointed out that the selective affinity for ERβ is greater than ERα. In addition, the binding mode indicated that the formation of hydrogen bond and hydrophobic interaction have an important effect on the stability of the complexes. Further, the calculation and decomposition of binding free energy explored the main contribution interactions to the total free energy.

MOLECULAR DYNAMICS AND FREE ENERGY ANALYSES OF ERK2–PYRAZOLYLPYRROLE INHIBITORS INTERACTIONS: INSIGHT INTO STRUCTURE-BASED LIGAND DESIGN

2009 ◽  
Vol 08 (05) ◽  
pp. 887-908 ◽  
Author(s):  
JIN-HUI ZHAN ◽  
XI ZHAO ◽  
XU-RI HUANG ◽  
CHIA-CHUNG SUN
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Signal Transduction Pathway ◽  
Binding Mode ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Protein Motions ◽  
Extracellular Signal

The extracellular signal-regulated protein kinase 2 (ERK2) is a pivotal member involving in Ras/Raf/MEK/ERK signal transduction pathway, acting as a central point where multiple signaling pathways coalesce to drive transcription. The pyrazolylpyrrole compounds as ATP competitive inhibitors of ERK2 can bind target with a special binding mode and have higher inhibitory potency than other ERK2-inhibitors. We investigated the interaction mode of ERK2-inhibitor using molecular dynamics simulation. The molecular mechanics Poisson–Boltzmann surface area approach is used to calculate the binding free energy of ERK2 with pyrazolylpyrrole inhibitors to analyze the factors of improving the affinity. The results indicated that the electrostatic interactions play the most important role in keeping the stabilization of ERK2-inhibitor. The structural analyses showed that the protein motions can be controlled by changing the structures of inhibitors; furthermore, the full use of available space in the binding site by improving the flexibilities of inhibitors and introducing hydrophobic groups can increase the inhibitory effect.

Insight into the adsorption profiles of the Saprolegnia monoica chitin synthase MIT domain on POPA and POPC membranes by molecular dynamics simulation studies

2016 ◽  
Vol 18 (7) ◽  
pp. 5281-5290 ◽  
Author(s):  
Guanglin Kuang ◽  
Lijun Liang ◽  
Christian Brown ◽  
Qi Wang ◽  
Vincent Bulone ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Chitin Synthase ◽  
Dynamics Simulation ◽  
Simulation Methods ◽  
Simulation Studies ◽  
Insight Into

The binding mode and binding free energy of the Saprolegnia monoica chitin synthase MIT domain with the POPA membrane have been studied by molecular simulation methods.

scholarly journals Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3054 ◽  
Author(s):  
Shailima Rampogu ◽  
Gihwan Lee ◽  
Ayoung Baek ◽  
Minky Son ◽  
Chanin Park ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Binding Free Energy ◽  
Heart Diseases ◽  
3D Qsar ◽  
Binding Mode ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
New Drugs ◽  
Dynamics Simulation ◽  
Discovery Studio

Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop new drugs to combat the disease. In this pursuit, the 3D QSAR ligand-pharmacophore (pharm 1) and receptor-based pharmacophore (pharm 2) search was initiated to retrieve the candidate compounds from universal natural compounds database. The validated models were allowed to map the universal natural compounds database. The obtained lead candidates were subjected to molecular docking against cysteine protease (PDB code: 1ME3) employing -Cdocker available on the discovery studio. Subsequently, two Hits have satisfied the selection criteria and were escalated to molecular dynamics simulation and binding free energy calculations. These Hits have demonstrated higher dock scores, displayed interactions with the key residues portraying an ideal binding mode complemented by mapping to all the features of pharm 1 and pharm 2. Additionally, they have rendered stable root mean square deviation (RMSD) and potential energy profiles illuminating their potentiality as the prospective antichagastic agents. The study further demonstrates the mechanism of inhibition by tetrad residues compromising of Gly23 and Asn70 holding the ligand at each ends and the residues Gly65 and Gly160 clamping the Hits at the center. The notable feature is that the Hits lie in close proximity with the residues Glu66 and Leu67, accommodating within the S1, S2 and S3 subsites. Considering these findings, the study suggests that the Hits may be regarded as effective therapeutics against Chagas disease.

scholarly journals Phytochemical Moieties From Indian Traditional Medicine for Targeting Dual Hotspots on SARS-CoV-2 Spike Protein: An Integrative in-silico Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
V. Umashankar ◽  
Sanjay H. Deshpande ◽  
Harsha V. Hegde ◽  
Ishwar Singh ◽  
Debprasad Chattopadhyay
Keyword(s):  
Free Energy ◽  
Binding Energy ◽  
Traditional Medicine ◽  
Binding Affinity ◽  
In Silico ◽  
Binding Free Energy ◽  
Contemporary Literature ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Syzygium Aromaticum

SARS-CoV-2 infection across the world has led to immense turbulence in the treatment modality, thus demanding a swift drug discovery process. Spike protein of SARS-CoV-2 binds to ACE2 receptor of human to initiate host invasion. Plethora of studies demonstrate the inhibition of Spike-ACE2 interactions to impair infection. The ancient Indian traditional medicine has been of great interest of Virologists worldwide to decipher potential antivirals. Hence, in this study, phytochemicals (1,952 compounds) from eight potential medicinal plants used in Indian traditional medicine were meticulously collated, based on their usage in respiratory disorders, along with immunomodulatory and anti-viral potential from contemporary literature. Further, these compounds were virtually screened against Receptor Binding Domain (RBD) of Spike protein. The potential compounds from each plant were prioritized based on the binding affinity, key hotspot interactions at ACE2 binding region and glycosylation sites. Finally, the potential hits in complex with spike protein were subjected to Molecular Dynamics simulation (450 ns), to infer the stability of complex formation. Among the compounds screened, Tellimagrandin-II (binding energy of −8.2 kcal/mol and binding free energy of −32.08 kcal/mol) from Syzygium aromaticum L. and O-Demethyl-demethoxy-curcumin (binding energy of −8.0 kcal/mol and binding free energy of −12.48 kcal/mol) from Curcuma longa L. were found to be highly potential due to their higher binding affinity and significant binding free energy (MM-PBSA), along with favorable ADMET properties and stable intermolecular interactions with hotspots (including the ASN343 glycosylation site). The proposed hits are highly promising, as these are resultant of stringent in silico checkpoints, traditionally used, and are documented through contemporary literature. Hence, could serve as promising leads for subsequent experimental validations.

Virtual Compound Screening and Molecular Dynamics to Identify New Inhibitors for Human Glutathione Reductase

2020 ◽  
Vol 17 (12) ◽  
pp. 1465-1474
Author(s):  
Mohsen Sargolzaei
Keyword(s):  
Oxidative Stress ◽  
Molecular Dynamics ◽  
Free Energy ◽  
Glutathione Reductase ◽  
Binding Free Energy ◽  
Rational Drug Design ◽  
Dynamics Simulation ◽  
Reductase Inhibitors ◽  
Free Energy Decomposition

Background: Oxidative stress is a defense mechanism against malarial intracellular parasite infection. On the other hand, the Human glutathione reductase enzyme reduces oxidative stress in the cells, making the inhibitors of this enzyme a promising candidate for malaria treatment. Objective: Rational drug design was used in this work to plan new human glutathione reductase inhibitors. Methods: Virtual screening was performed using the ZINC database and molecular docking was used to detect appropriate human glutathione reductase inhibitors. Based on the docking scores obtained, the top three highest-ranked ligands were selected for the molecular dynamics simulation study. The MD simulation was performed for each complex in a length of 100 ns. Results: RMSD, RMSF and hydrogen bond analyzes were performed on the derived trajectories. Molecular mechanics generalized born surface area (MM-GBSA) and pairwise per-residue free energy decomposition analyzes were performed for the determination of binding free energy and the determination of dominant residues involved in the binding process, respectively. The binding free energy analysis showed that the molecule of 3-((7-(furan-2-ylmethyl)-5,6-diphenyl-7H-pyrrolo[2,3- d] pyrimidin-4-yl) amino) propan-1-ol is the most potent inhibitor among the molecules considered against human glutathione reductase enzyme. Conclusion: This molecule can be considered a novel candidate for antimalarial treatments.

Sign in / Sign up

Export Citation Format

Share Document