scholarly journals Investigating the role of N-terminal domain in phosphodiesterase 4B-inhibition by molecular dynamics simulation

2020 ◽  
Author(s):  
Vidushi Sharma ◽  
Sharad Wakode
Keyword(s):  
Ligand Binding ◽  
Root Mean Square ◽  
Active Site ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Sequence Identity ◽  
Terminal Domain ◽  
Phosphodiesterase 4B

AbstractPhosphodiesterase 4B (PDE4B) is a potential therapeutic target for the inflammatory respiratory diseases such as congestive obstructive pulmonary disease (COPD) and asthma. The sequence identity of ∼88% with its isoform PDE4D is the key barrier in developing selective PDE4B inhibitors which may help to overcome associated side effects. Despite high sequence identity, both isoforms differ in few residues present in N-terminal (UCR2) and C-terminal (CR3) involved in catalytic site formation. Previously, we designed and tested specific PDE4B inhibitors considering N-terminal residues as a part of the catalytic cavity. In continuation, current work thoroughly presents an MD simulation-based analysis of N-terminal residues and their role in ligand binding. The various parameters viz. root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), principal component analysis (PCA), dynamical cross-correlation matrix (DCCM) analysis, secondary structure analysis, and residue interaction mapping were investigated to establish rational. Results showed that UCR2 reduced RMSF values for the metal binding pocket (31.5±11 to 13.12±6 Å2) and the substrate-binding pocket (38.8±32 to 17.3±11 Å2). UCR2 enhanced anti-correlated motion at the active site region that led to the improved ligand-binding affinity of PDE4B from −24.57±3 to −35.54±2 kcal/mol. Further, the atomic-level analysis indicated that T-pi and π-π interactions between inhibitors and residues are vital forces that regulate inhibitor association to PDE4B with high affinity. In conclusion, UCR2, the N-terminal domain, embraces the dynamics of PDE4B active site and stabilizes PDE4B inhibitor interactions. Therefore the N-terminal domain needs to be included by designing next-generation, selective PDE4B-inhibitors as potential anti-inflammatory drugs.

scholarly journals Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4829
Author(s):  
Sajjad Haider ◽  
Assem Barakat ◽  
Zaheer Ul-Haq
Keyword(s):  
Virtual Screening ◽  
Molecular Dynamic ◽  
Root Mean Square ◽  
Cancer Metastasis ◽  
Pharmacophore Model ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Dynamic Simulations

CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and in-house databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.

scholarly journals Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

2021 ◽  
Vol 1 ◽  
Author(s):  
Shafi Mahmud ◽  
Md. Robiul Hasan ◽  
Suvro Biswas ◽  
Gobindo Kumar Paul ◽  
Shamima Afrose ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Global Economy ◽  
Transmission Rate ◽  
Accessible Surface Area ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Protease Inhibition ◽  
Main Protease

Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of −8.3, −8.6, and −8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.

scholarly journals Reappraisal of Trifluperidol against NSP-3 protein: Potential therapeutic for COVID-19

2020 ◽  
Author(s):  
Ajita Pandey
Keyword(s):  
Root Mean Square ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Scoring Functions ◽  
Mean Square ◽  
Structural Protein ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Novel coronavirus disease 2019 (COVID-19) is a highly infectious disease that is caused by the recently discovered severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Because there are no specific vaccines or drugs for SARS-CoV-2, drug repurposing may be a promising approach. SARS-CoV-2 has a positive-sense RNA genome that encodes non-structural proteins (Nsps), which are essential for viral replication in the host cell. Non-structural protein 3 (Nsp3) is a multidomain protein and is the largest protein of the replicase complex. Nsp3 contains an ADP-ribose phosphatase (ADRP) domain, also called the macrodomain, which interferes with the host immune response. In the present study, we used computational regression methods to target the ADRP domain of Nsp3, using FDA-approved drugs. We virtually screened 2,892 FDA-approved drugs, using a combination of molecular docking and scoring functions. Saquinavir and trifluperidol were identified as potential leads and were further investigated using molecular dynamics simulation (MDS) to predict the stability and behavior of the ADRP-drug complexes. Analysis of root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and number of hydrogen bonds showed that the ADRP-trifluperidol complex is more stable than the ADRP-saquinavir complex. The screening and the MDS results suggest that trifluperidol is a novel inhibitor of the ADRP domain of Nsp3. Trifluperidol could, therefore, potentially be used to help control the spread of COVID-19, either alone or in combination with antiviral agents. Further in-vitro and in-vivo experiments are necessary to confirm our in silico results.

scholarly journals Efficacy of Phytochemicals Derived from Avicennia officinalis for the Management of COVID-19: A Combined In Silico and Biochemical Study

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2210
Author(s):  
Shafi Mahmud ◽  
Gobindo Kumar Paul ◽  
Mirola Afroze ◽  
Shirmin Islam ◽  
Swagota Briti Ray Gupt ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Antioxidant Activities ◽  
Binding Free Energy ◽  
Healthcare Management ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Main Protease ◽  
Avicennia Officinalis

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.

scholarly journals Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5304
Author(s):  
Mohammad G. Al-Thiabat ◽  
Amirah Mohd Gazzali ◽  
Noratiqah Mohtar ◽  
Vikneswaran Murugaiyah ◽  
Ezatul Ezleen Kamarulzaman ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Folic Acid ◽  
Root Mean Square ◽  
Active Site ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Cancer Drug ◽  
Radius Of Gyration ◽  
Mean Square ◽  
The Stability

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < −15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA–βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9–2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0–100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149–151) compared to FA–FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.

scholarly journals Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

2016 ◽  
Vol 14 (1) ◽  
pp. 188-196 ◽  
Author(s):  
Syed Lal Badshah ◽  
Abdul Naeem Khan ◽  
Yahia Nasser Mabkhot
Keyword(s):  
Molecular Dynamics ◽  
Secondary Structure ◽  
Cholera Toxin ◽  
Root Mean Square ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Toxin A

AbstractA molecular dynamics (MD) simulation study of the enzymatic portion of cholera toxin; cholera toxin A-1 polypeptide (CTA1) was performed at 283, 310 and 323 K. From total energy analysis it was observed that this toxin is stable thermodynamically and these outcomes were likewise confirmed by root mean square deviations (RMSD) investigations. The Cα root mean square fluctuation (RMSF) examinations revealed that there are a number of residues inside CTA1, which can be used as target for designing and synthesizing inhibitory drugs, in order to inactivate cholera toxin inside the human body. The fluctuations in the radius of gyration and hydrogen bonding in CTA1 proved that protein unfolding and refolding were normal routine phenomena in its structure at all temperatures. Solvent accessible surface area study identified the hydrophilic nature of the CTA1, and due to this property it can be a potential biological weapon. The structural identification (STRIDE) algorithm for proteins was successfully used to determine the partially disordered secondary structure of CTA1. On account of this partially disordered secondary structure, it can easily deceive the proteolytic enzymes of the endoplasmic reticulum of host cells.

scholarly journals GNINA 1.0: molecular docking with deep learning

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Andrew T. McNutt ◽  
Paul Francoeur ◽  
Rishal Aggarwal ◽  
Tomohide Masuda ◽  
Rocco Meli ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Root Mean Square ◽  
Root Mean Square Deviation ◽  
Computational Cost ◽  
Scoring Function ◽  
Binding Pocket ◽  
Protein Docking ◽  
Mean Square ◽  
Mean Square Deviation ◽  
Autodock Vina

AbstractMolecular docking computationally predicts the conformation of a small molecule when binding to a receptor. Scoring functions are a vital piece of any molecular docking pipeline as they determine the fitness of sampled poses. Here we describe and evaluate the 1.0 release of the Gnina docking software, which utilizes an ensemble of convolutional neural networks (CNNs) as a scoring function. We also explore an array of parameter values for Gnina 1.0 to optimize docking performance and computational cost. Docking performance, as evaluated by the percentage of targets where the top pose is better than 2Å root mean square deviation (Top1), is compared to AutoDock Vina scoring when utilizing explicitly defined binding pockets or whole protein docking. Gnina, utilizing a CNN scoring function to rescore the output poses, outperforms AutoDock Vina scoring on redocking and cross-docking tasks when the binding pocket is defined (Top1 increases from 58% to 73% and from 27% to 37%, respectively) and when the whole protein defines the binding pocket (Top1 increases from 31% to 38% and from 12% to 16%, respectively). The derived ensemble of CNNs generalizes to unseen proteins and ligands and produces scores that correlate well with the root mean square deviation to the known binding pose. We provide the 1.0 version of Gnina under an open source license for use as a molecular docking tool at https://github.com/gnina/gnina.

scholarly journals Effects of the Temperature and the pH on the Main Protease of SARS-CoV-2: A Molecular Dynamics Simulation Study

2021 ◽  
Vol 12 (6) ◽  
pp. 7239-7248
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Root Mean Square ◽  
Dynamics Simulation ◽  
Effect Of Temperature ◽  
Water Molecules ◽  
Mean Square ◽  
Main Protease ◽  
Decreasing Ph ◽  
Increasing Temperature

The novel coronavirus, recognized as COVID-19, is the cause of an infection outbreak in December 2019. The effect of temperature and pH changes on the main protease of SARS-CoV-2 were investigated using all-atom molecular dynamics simulation. The obtained results from the root mean square deviation (RMSD) and root mean square fluctuations (RMSF) analyses showed that at a constant temperature of 25℃ and pH=5, the conformational change of the main protease is more significant than that of pH=6 and 7. Also, by increasing temperature from 25℃ to 55℃ at constant pH=7, a remarkable change in protein structure was observed. The radial probability of water molecules around the main protease was decreased by increasing temperature and decreasing pH. The weakening of the binding energy between the main protease and water molecules due to the increasing temperature and decreasing pH has reduced the number of hydrogen bonds between the main protease and water molecules. Finding conditions that alter the conformation of the main protease could be fundamental because this change could affect the virus’s functionality and its ability to impose illness.

Xanthine oxidase inhibitory activity of Euphorbia peplus L. phenolics

2021 ◽  
Vol 24 ◽  
Author(s):  
Emadeldin M. Kamel ◽  
Noha A. Ahmed ◽  
Ashraf A. El-Bassuony ◽  
Omnia E. Hussein ◽  
Barakat Alrashdi ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Active Site ◽  
Inhibitory Activity ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Euphorbia Peplus

Background: Various phenolics show inhibitory activity towards xanthine oxidase (XO), an enzyme that generates reactive oxygen species which cause oxidative damage. Objective: This study investigated the XO inhibitory activity of Euphorbia peplus phenolics. Methods: The dried powdered aerial parts of E. peplus were extracted, fractioned and phenolics were isolated and identified. The XO inhibitory activity of E. peplus extract (EPE) and the isolated phenolics was investigated in vitro and in vivo. Results: Three phenolics were isolated from the ethyl acetate fraction of E. peplus. All isolated compounds and the EPE showed inhibitory activity towards XO in vitro. In hyperuricemic rats, EPE and the isolated phenolics decreased uric acid and XO activity. Molecular docking showed the binding modes of isolated phenolics with XO, depicting significant interactions with the active site amino acid residues. Molecular dynamics simulation trajectories confirmed the interaction of isolated phenolics with XO by forming hydrogen bonds with the active site residues. Also, the root mean square (RMS) deviations of XO and phenolics-XO complexes achieved equilibrium and fluctuated during the 10 ns MD simulations. The radius of gyration and solvent accessible surface area investigations showed that different systems were stabilized at ≈ 2500 ps. The RMS fluctuations profile depicted that the drug binding site exhibited a rigidity behavior during the simulation. Conclusion: In vitro, in vivo and computational investigations showed the XO inhibitory activity of E. peplus phenolics. These phenolics might represent promising candidates for the development of XO inhibitors.

scholarly journals Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases

2020 ◽  
Vol 295 (20) ◽  
pp. 6972-6982
Author(s):  
Dakshinamurthy Sivakumar ◽  
Vikash Kumar ◽  
Michael Naumann ◽  
Matthias Stein
Keyword(s):  
Active Site ◽  
Electrostatic Interactions ◽  
Active Form ◽  
Cysteine Proteases ◽  
Binding Pocket ◽  
Catalytic Triad ◽  
Catalytic Site ◽  
Dynamics Simulation ◽  
Active Site Residues ◽  
Catalytically Active

The ovarian tumor domain (OTU) deubiquitinylating cysteine proteases OTUB1 and OTUB2 (OTU ubiquitin aldehyde binding 1 and 2) are representative members of the OTU subfamily of deubiquitinylases. Deubiquitinylation critically regulates a multitude of important cellular processes, such as apoptosis, cell signaling, and growth. Moreover, elevated OTUB expression has been observed in various cancers, including glioma, endometrial cancer, ovarian cancer, and breast cancer. Here, using molecular dynamics simulation approaches, we found that both OTUB1 and OTUB2 display a catalytic triad characteristic of proteases but differ in their configuration and protonation states. The OTUB1 protein had a prearranged catalytic site, with strong electrostatic interactions between the active-site residues His265 and Asp267. In OTUB2, however, the arrangement of the catalytic triad was different. In the absence of ubiquitin, the neutral states of the catalytic-site residues in OTUB2 were more stable, resulting in larger distances between these residues. Only upon ubiquitin binding did the catalytic triad in OTUB2 rearrange and bring the active site into a catalytically feasible state. An analysis of water access channels revealed only a few diffusion trajectories for the catalytically active form of OTUB1, whereas in OTUB2 the catalytic site was solvent-accessible, and a larger number of water molecules reached and left the binding pocket. Interestingly, in OTUB2, the catalytic residues His224 and Asn226 formed a stable hydrogen bond. We propose that the observed differences in activation kinetics, protonation states, water channels, and active-site accessibility between OTUB1 and OTUB2 may be relevant for the selective design of OTU inhibitors.

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