scholarly journals A Comparative Study of Binding of Different Drugs on gp120: Insight from Molecular Dynamics Simulation Study

2018 ◽  
Vol 34 (6) ◽  
pp. 2954-2962
Author(s):  
Vishnudatt Pandey ◽  
Gargi Tiwari ◽  
Rajendra Prasad Ojha
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Binding Sites ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Receptor Protein ◽  
Contact Points ◽  
Gp120 Binding ◽  
Cd4 Binding Site ◽  
Dynamics Simulations

HIV-I cellular infection triggered by CD4 receptor protein and viral envelop glycoprotein gp120 binding event. CD4:gp120 surface is directed by the contact points of a hydrophobic gp120 cavity capped by Phe43CD4 and ionic bonds residues Arg59CD4 and Asp368gp120. The binding sites originated by gp120 and CD4 interaction leads to the entry of HIV-I into the host membrane, where, gp120 and a CD4 binding site becomes the main mark for plenty of drug uncovering program. Here, we took the crystal structure of small-molecule of gp120 in a complex that concurrently pursues both of the hotspots of gp120 binding sites. All ligands in our study are small molecules that are able to obstruct the protein-protein interactions between CD4 and gp120. This study aims at the thermodynamical insights of the ligand binding in CD4 binding sites using Molecular Dynamics Simulations Study and calculation of binding free energy. The physical of binding of drugs distinctly indicates a hydrophobic and electrostatics interaction motivated binding of ligands which explicitly mark CD4 binding sites.

MOLECULAR MODELING OF THE INTERACTIONS BETWEEN HISTONE DEACETYLASE 8 AND INHIBITORS

2012 ◽  
Vol 11 (04) ◽  
pp. 907-924 ◽  
Author(s):  
DAWEI HUANG ◽  
XIAOHUI LI ◽  
ZHILONG XIU
Keyword(s):  
Molecular Dynamics ◽  
Histone Deacetylases ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Zinc Ion ◽  
Dynamics Simulation ◽  
Amino Acid Residues ◽  
Domain Docking ◽  
Dynamics Simulations ◽  
Linker Domain

Inhibitors of histone deacetylases (HDACs) have become an attractive class of anticancer agent. To understand the interaction between HDAC8 and inhibitors, including "pan-" inhibitors that inhibit many HDACs isoforms and selective inhibitors with no linker domain, docking and molecular dynamics simulation were conducted. Docking results showed the presence of π-π interactions between "linkerless" inhibitors and the aromatic amino acid residues of HDAC8 in the active site. Binding between HDAC8 and inhibitors was also stabilized by hydrogen bond and hydrophobic interaction. In molecular dynamics simulations, the zinc ion was shown to coordinate one more atom of HDAC8-"linkerless" inhibitor complexes than HDAC8-"pan-" inhibitor complexes. Persistent hydrogen bonds also existed between Tyr306 of HDAC8 and some inhibitors. When inhibitors with large cap groups bound to the active pocket of HDAC8, Phe152 and Met274 shifted from their initial positions and the entrance of the active pocket became more open, resulting in the formation of sub-pocket. Hydrophobic interactions contributed most favorably to the binding free energy between HDAC8 and inhibitors. Lys33, Asp178, Asp267, Tyr306 and Leu308 of HDAC8 were favorable for binding with all inhibitors.

Homology modeling of mouse NLRP3 NACHT protein domain and molecular dynamics simulation of its ATP binding properties

2020 ◽  
Vol 31 (03) ◽  
pp. 2050036
Author(s):  
Hien T. T. Lai ◽  
Do Minh Ha ◽  
Duc Manh Nguyen ◽  
Toan T. Nguyen
Keyword(s):  
Molecular Dynamics ◽  
Homology Modeling ◽  
Structural Model ◽  
Protein Domain ◽  
New Drugs ◽  
Dynamics Simulation ◽  
Receptor Protein ◽  
Caspase 1 ◽  
Dynamics Simulations ◽  
Msu Crystals

Gout is an extremely painful form of inflammatory arthritis, caused by the formation of monosodium urate (MSU) crystals in the joints. MSU crystals are one of the triggers for the activation of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome (NACHT, LRR and PYD domains-containing protein), which in turn induces caspase-1 activation and a nonspecific immune responses that cause inflammation. Further structural studies and ligand designs are needed to block the interaction of NLRP3 with MSU or allow the interaction without activating caspase-1. This would facilitate the screening of new drugs for the treatment of gout. Using computational methods for homology modeling and molecular dynamics simulations, the structural model of mouse NLRP3 protein with its domains, three potential structural models were consistently constructed and tested to find the most stable structural model. Adenosine triphosphate (ATP) — an activator of NACHT (the central domain of mouse NLRP3 protein) — was docked and simulated. Ligand effects to activate as well as limit this protein were analyzed. This study provides insights to deeper understanding about gout development pathway via the NLRP3 protein.

scholarly journals Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5696
Author(s):  
Wei Lim Chong ◽  
Koollawat Chupradit ◽  
Sek Peng Chin ◽  
Mai Mai Khoo ◽  
Sook Mei Khor ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Protein Binding ◽  
Protein Interactions ◽  
Binding Free Energy ◽  
Single Point ◽  
Md Simulations ◽  
Nanoparticle Tracking Analysis ◽  
Buffer Solution ◽  
Dynamics Simulations

Protein-protein interaction plays an essential role in almost all cellular processes and biological functions. Coupling molecular dynamics (MD) simulations and nanoparticle tracking analysis (NTA) assay offered a simple, rapid, and direct approach in monitoring the protein-protein binding process and predicting the binding affinity. Our case study of designed ankyrin repeats proteins (DARPins)—AnkGAG1D4 and the single point mutated AnkGAG1D4-Y56A for HIV-1 capsid protein (CA) were investigated. As reported, AnkGAG1D4 bound with CA for inhibitory activity; however, it lost its inhibitory strength when tyrosine at residue 56 AnkGAG1D4, the most key residue was replaced by alanine (AnkGAG1D4-Y56A). Through NTA, the binding of DARPins and CA was measured by monitoring the increment of the hydrodynamic radius of the AnkGAG1D4-gold conjugated nanoparticles (AnkGAG1D4-GNP) and AnkGAG1D4-Y56A-GNP upon interaction with CA in buffer solution. The size of the AnkGAG1D4-GNP increased when it interacted with CA but not AnkGAG1D4-Y56A-GNP. In addition, a much higher binding free energy (∆GB) of AnkGAG1D4-Y56A (−31 kcal/mol) obtained from MD further suggested affinity for CA completely reduced compared to AnkGAG1D4 (−60 kcal/mol). The possible mechanism of the protein-protein binding was explored in detail by decomposing the binding free energy for crucial residues identification and hydrogen bond analysis.

scholarly journals Exploring the Binding Interaction of Raf Kinase Inhibitory Protein With the N-Terminal of C-Raf Through Molecular Docking and Molecular Dynamics Simulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Shraddha Parate ◽  
Shailima Rampogu ◽  
Gihwan Lee ◽  
Jong Chan Hong ◽  
Keun Woo Lee
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Sites ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Web Servers ◽  
Inhibitory Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitory Protein

Protein-protein interactions are indispensable physiological processes regulating several biological functions. Despite the availability of structural information on protein-protein complexes, deciphering their complex topology remains an outstanding challenge. Raf kinase inhibitory protein (RKIP) has gained substantial attention as a favorable molecular target for numerous pathologies including cancer and Alzheimer’s disease. RKIP interferes with the RAF/MEK/ERK signaling cascade by endogenously binding with C-Raf (Raf-1 kinase) and preventing its activation. In the current investigation, the binding of RKIP with C-Raf was explored by knowledge-based protein-protein docking web-servers including HADDOCK and ZDOCK and a consensus binding mode of C-Raf/RKIP structural complex was obtained. Molecular dynamics (MD) simulations were further performed in an explicit solvent to sample the conformations for when RKIP binds to C-Raf. Some of the conserved interface residues were mutated to alanine, phenylalanine and leucine and the impact of mutations was estimated by additional MD simulations and MM/PBSA analysis for the wild-type (WT) and constructed mutant complexes. Substantial decrease in binding free energy was observed for the mutant complexes as compared to the binding free energy of WT C-Raf/RKIP structural complex. Furthermore, a considerable increase in average backbone root mean square deviation and fluctuation was perceived for the mutant complexes. Moreover, per-residue energy contribution analysis of the equilibrated simulation trajectory by HawkDock and ANCHOR web-servers was conducted to characterize the key residues for the complex formation. One residue each from C-Raf (Arg398) and RKIP (Lys80) were identified as the druggable “hot spots” constituting the core of the binding interface and corroborated by additional long-time scale (300 ns) MD simulation of Arg398Ala mutant complex. A notable conformational change in Arg398Ala mutant occurred near the mutation site as compared to the equilibrated C-Raf/RKIP native state conformation and an essential hydrogen bonding interaction was lost. The thirteen binding sites assimilated from the overall analysis were mapped onto the complex as surface and divided into active and allosteric binding sites, depending on their location at the interface. The acquired information on the predicted 3D structural complex and the detected sites aid as promising targets in designing novel inhibitors to block the C-Raf/RKIP interaction.

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>

Drug resistance mechanisms of three mutations V32I, I47V and V82I in HIV-1 protease toward inhibitors probed by molecular dynamics simulations and binding free energy predictions

RSC Advances ◽  
2016 ◽  
Vol 6 (63) ◽  
pp. 58573-58585 ◽  
Author(s):  
Jianzhong Chen
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Binding Free Energy ◽  
Resistance Mechanisms ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Probe Drug ◽  
Dynamics Simulations ◽  
Hiv 1

Molecular dynamics simulation and binding free energy calculations were used to probe drug resistance of HIV-1 protease mutations toward inhibitors.

scholarly journals Formation Mechanism of Ion Channel in Channelrhodopsin-2: Molecular Dynamics Simulation and Steering Molecular Dynamics Simulations

2019 ◽  
Vol 20 (15) ◽  
pp. 3780 ◽  
Author(s):  
Ting Yang ◽  
Wenying Zhang ◽  
Jie Cheng ◽  
Yanhong Nie ◽  
Qi Xin ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ion Channel ◽  
Molecular Dynamics Simulations ◽  
Formation Mechanism ◽  
Binding Sites ◽  
Electrostatic Interactions ◽  
Potential Of Mean Force ◽  
Dynamics Simulation ◽  
Cationic Channel ◽  
Dynamics Simulations

Channelrhodopsin-2 (ChR2) is a light-activated and non-selective cationic channel protein that can be easily expressed in specific neurons to control neuronal activity by light. Although ChR2 has been extensively used as an optogenetic tool in neuroscience research, the molecular mechanism of cation channel formation following retinal photoisomerization in ChR2 is not well understood. In this paper, studies of the closed and opened state ChR2 structures are presented. The formation of the cationic channel is elucidated in atomic detail using molecular dynamics simulations on the all-trans-retinal (ChR2-trans) configuration of ChR2 and its isomerization products, 13-cis-retinal (ChR2-cis) configuration, respectively. Photoisomerization of the retinal-chromophore causes the destruction of interactions among the crucial residues (e.g., E90, E82, N258, and R268) around the channel and the extended H-bond network mediated by numerous water molecules, which opens the pore. Steering molecular dynamics (SMD) simulations show that the electrostatic interactions at the binding sites in intracellular gate (ICG) and central gate (CG) can influence the transmembrane transport of Na+ in ChR2-cis obviously. Potential of mean force (PMF) constructed by SMD and umbrella sampling also found the existing energy wells at these two binding sites during the transportation of Na+. These wells partly hinder the penetration of Na+ into cytoplasm through the ion channel. This investigation provides a theoretical insight on the formation mechanism of ion channels and the mechanism of ion permeation.

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>

Molecular dynamics simulation and free energy analysis of the interaction of platinum-based anti-cancer drugs with DNA

2016 ◽  
Vol 15 (06) ◽  
pp. 1650054 ◽  
Author(s):  
Seifollah Jalili ◽  
Mina Maddah ◽  
Jeremy Schofield
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Hydrogen Bonds ◽  
Binding Free Energy ◽  
Double Helix ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Cancer Drugs ◽  
Anti Cancer ◽  
Dynamics Simulations

Cisplatin and oxaliplatin are two widely-used anti-cancer drugs which covalently bind to a same location in DNA strands. Platinum agents make intrastrand and interstrand cross-links with the N7 atoms of guanine nucleotides which prevent DNA from polymerization by causing a distortion in the double helix. Molecular dynamics simulations and free energy calculations were carried out to investigate the binding of two platinum-based anti-cancer drugs with DNA. We compared the binding of these drugs which differ in their carrier ligands, and hence their potential interactions with DNA. When a platinum agent binds to nucleotides, it causes a high amount of deformation in DNA structure. To find the extent of deformation, torsion angles and base pair and groove parameters of DNA were considered. These parameters were compared with normal B-DNA which was considered as the undamaged DNA. The formation of hydrogen bonds between drugs and DNA nucleotides was examined in solution. It was shown that oxaliplatin forms more hydrogen bonds than cisplatin. Our results confirm that the structure of the platinated DNA rearranges significantly and cisplatin tries to deform DNA more than oxaliplatin. The binding free energies were also investigated to understand the affinities, types and the contributions of interactions between drugs and DNA. It was concluded that oxaliplatin tendency for binding to DNA is more than cisplatin in solvent environment. The binding free energy was calculated based on the MM/PBSA and MM/GBSA methods and the results of QM/MM calculations verified them.

scholarly journals Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease

2021 ◽  
Author(s):  
Ahmed Ali Al-Karmalawy ◽  
Radwan Alnajjar ◽  
Mohammed Dahab ◽  
Ahmed Metwaly ◽  
Ibrahim Eissa
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Free Energy ◽  
Solvent Accessibility ◽  
Genetic Material ◽  
New Drugs ◽  
Dynamics Simulation ◽  
Main Protease ◽  
Natural Inhibitor ◽  
Dynamics Simulations

Background: Drug repurposing is the fastest effective method to provide treatment for coronavirus disease (COVID-19). Drugs that targeting a closely related virus with similar genetic material such as hepatitis C virus (HCV) and more specifically targeting a similar viral protease would be an excellent choice. Methods: In this study, we carried out a virtual screening for fifteen anti HCV drugs against COVID-19 main protease using computational molecular docking techniques. Moreover, Velpatasvir (4) and Sofosbuvir (13) drugs were further evaluated through molecular dynamics simulations followed by calculating the binding free energy using the molecular mechanics generalised born/solvent accessibility (MM-GBSA) approach. Results: The binding affinity descending order was N3 natural inhibitor (1), Velpatasvir (4), Sofosbuvir (13), Ombitasvir (3), Glecaprevir (2), Asunaprevir (8), Paritaprevir (10), Grazoprevir (11), Elbasvir (6), Ledipasvir (5), Daclatasvir (7), Pibrentasvir (9), Simeprevir (12), Dasabuvir (14), Taribavirin (16) and finally Ribavirin (15). Molecular dynamics simulation reveals that Sofosbuvir (13) has exciting properties and it was stable within the active site; it also showed good MM-GBSA compared to the natural inhibitor N3. Conclusion: Our results could be auspicious for fast repurposing of the examined drugs either alone or in combinations with each other for the treatment of the COVID-19. Furthermore, this work provides a clear spot on the structure-activity relationship (SAR) for targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease and helps the design and synthesis of new drugs in the future targeting it as well.

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