Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor: Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

Phosphatidylinositol 3-kinase δ (PI3Kδ) is a validated drug target for the treatment of cancer. The present study aims to search for new inhibitors of PI3Kδ by employing pharmacophore modelling using LigandScout Advanced 4.3 software. The three hydrogen bond acceptors and two hydrophobic features were proposed as a pharmacophore model using LASW1976 structure. The model was then validated using the Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) and GH score. It was used to screen new molecules in the ZINC database, which resulted in 599 hits. All 599 hits were then docked into PI3Kδ protein, and five best hits were submitted to 50 ns molecular dynamics simulations. Each hit complexed with PI3Kδ underwent minor conformational changes as indicated by the values of Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF). Furthermore, prediction of the binding free energy using Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) method showed that five hits, i.e., Lig25/ZINC253496376, Lig682/ZINC98047241, Lig449/ZINC85878047, Lig554/ZINC253389510, and Lig199/ZINC12638303, had lower binding energy compared to LASW1976. This result indicated their potentials as new inhibitors of PI3Kδ.

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Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak

Bulletin of the National Research Centre ◽

10.1186/s42269-020-00479-6 ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Mohammad Mahfuz Ali Khan Shawan ◽

Sajal Kumar Halder ◽

Md. Ashraful Hasan

Keyword(s):

Molecular Dynamics ◽

Root Mean Square ◽

In Silico ◽

Binding Free Energy ◽

Biologically Active ◽

Dynamics Simulation ◽

Mean Square ◽

Efficient Treatment ◽

Target Proteins

Abstract Background At present, the entire world is in a war against COVID-19 pandemic which has gradually led us toward a more compromised “new normal” life. SARS-CoV-2, the pathogenic microorganism liable for the recent COVID-19 outbreak, is extremely contagious in nature resulting in an unusual number of infections and death globally. The lack of clinically proven therapeutic intervention for COVID-19 has dragged the world’s healthcare system into the biggest challenge. Therefore, development of an efficient treatment scheme is now in great demand. Screening of different biologically active plant-based natural compounds could be a useful strategy for combating this pandemic. In the present research, a collection of 43 flavonoids of 7 different classes with previously recorded antiviral activity was evaluated via computational and bioinformatics tools for their impeding capacity against SARS-CoV-2. In silico drug likeness, pharmacophore and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile analysis of the finest ligands were carried out using DataWarrior, DruLiTo and admetSAR programs, respectively. Molecular docking was executed by AutoDock Vina, while molecular dynamics simulation of the target protein–ligand bound complexes was done using nanoscalable molecular dynamics and visual molecular dynamics software package. Finally, the molecular target analysis of the selected ligands within Homo sapiens was conducted with SwissTargetPredcition web server. Results Out of the forty-three flavonoids, luteolin and abyssinone II were found to develop successful docked complex within the binding sites of target proteins in terms of lowest binding free energy and inhibition constant. The root mean square deviation and root mean square fluctuation values of the docked complex displayed stable interaction and efficient binding between the ligands and target proteins. Both of the flavonoids were found to be safe for human use and possessed good drug likeness properties and target accuracy. Conclusions Conclusively, the current study proposes that luteolin and abyssinone II might act as potential therapeutic candidates for SARS-CoV-2 infection. In vivo and in vitro experiments, however, should be taken under consideration to determine the efficiency and to demonstrate the mechanism of action.

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Understanding the Effect of Structural Diversity in WRKY Transcription Factors on DNA Binding Efficiency through Molecular Dynamics Simulation

Biology ◽

10.3390/biology8040083 ◽

2019 ◽

Vol 8 (4) ◽

pp. 83

Author(s):

Akshay Singh ◽

Ajay Kumar Sharma ◽

Nagendra Kumar Singh ◽

Humira Sonah ◽

Rupesh Deshmukh ◽

...

Keyword(s):

Molecular Dynamics ◽

Dna Binding ◽

Root Mean Square ◽

Conformational Changes ◽

Higher Plants ◽

Crop Improvement ◽

Dynamics Simulation ◽

Type I ◽

Mean Square ◽

Different Types

A precise understanding of the molecular mechanism involved in stress conditions has great importance for crop improvement. Biomolecules, such as WRKY proteins, which are the largest transcription factor family that is widely distributed in higher plants, plays a significant role in plant defense response against various biotic and abiotic stressors. In the present study, an extensive homology-based three-dimensional model construction and subsequent interaction study of WRKY DNA-binding domain (DBD) in CcWRKY1 (Type I), CcWRKY51 (Type II), and CcWRKY70 (Type III) belonging to pigeonpea, a highly tolerant crop species, was performed. Evaluation of the generated protein models was done to check their reliability and accuracy based on the quantitative and qualitative parameters. The final model was subjected to investigate the comparative binding analysis of different types of WRKY–DBD with DNA-W-box (a cis-acting element) by protein–DNA docking and molecular dynamics (MD) simulation. The DNA binding specificity with WRKY variants was scrutinized through protein–DNA interaction using the HADDOCK server. The stability, as well as conformational changes of protein–DNA complex, was investigated through molecular dynamics (MD) simulations for 100 ns using GROMACS. Additionally, the comparative stability and dynamic behavior of each residue of the WRKY–DBD type were analyzed in terms of root mean square deviation (RMSD), root mean square fluctuation (RMSF)values of the backbone atoms for each frame taking the minimized structure as a reference. The details of DNA binding activity of three different types of WRKY–DBD provided here will be helpful to better understand the regulation of WRKY gene family members in plants.

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

Biointerface Research in Applied Chemistry ◽

10.33263/briac126.72397248 ◽

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.

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

Molecules ◽

10.3390/molecules25204829 ◽

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.

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Molecular Dynamics Simulation of Barnase: Contribution of Noncovalent Intramolecular Interaction to Thermostability

Mathematical Problems in Engineering ◽

10.1155/2013/504183 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Zhiguo Chen ◽

Yi Fu ◽

Wenbo Xu ◽

Ming Li

Keyword(s):

Molecular Dynamics ◽

Thermal Stability ◽

Molecular Dynamics Simulation ◽

Root Mean Square ◽

Clinical Medicine ◽

Intramolecular Interaction ◽

Salt Bridge ◽

Dynamics Simulation ◽

Mean Square ◽

Thermal Stability Of

Bacillus amyloliquefaciensribonuclease Barnase (RNase Ba) is a 12 kD (kilodalton) small extracellular ribonuclease. It has broad application prospects in agriculture, clinical medicine, pharmaceutical, and so forth. In this work, the thermal stability of Barnase has been studied using molecular dynamics simulation at different temperatures. The present study focuses on the contribution of noncovalent intramolecular interaction to protein stability and how they affect the thermal stability of the enzyme. Profiles of root mean square deviation and root mean square fluctuation identify thermostable and thermosensitive regions of Barnase. Analyses of trajectories in terms of secondary structure content, intramolecular hydrogen bonds and salt bridge interactions indicate distinct differences in different temperature simulations. In the simulations, Four three-member salt bridge networks (Asp8-Arg110-Asp12, Arg83-Asp75-Arg87, Lys66-Asp93-Arg69, and Asp54-Lys27-Glu73) have been identified as critical salt bridges for thermostability which are maintained stably at higher temperature enhancing stability of three hydrophobic cores. The study may help enlighten our knowledge of protein structural properties, noncovalent interactions which can stabilize secondary peptide structures or promote folding, and also help understand their actions better. Such an understanding is required for designing efficient enzymes with characteristics for particular applications at desired working temperatures.

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The Construction of Chimeric T-Cell Receptor with Spacer Base of Modeling Study of VHH and MUC1 Interaction

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/578128 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Nazanin Pirooznia ◽

Sadegh Hasannia ◽

Majid Taghdir ◽

Fatemeh Rahbarizadeh ◽

Morteza Eskandani

Keyword(s):

Root Mean Square ◽

Conformational Changes ◽

Cell Receptor ◽

Dynamics Simulation ◽

Specific Response ◽

Conformational Structure ◽

Mean Square ◽

Chimeric Receptors ◽

Cell Immunotherapy ◽

And Function

Adaptive cell immunotherapy with the use of chimeric receptors leads to the best and most specific response against tumors. Chimeric receptors consist of a signaling fragment, extracellular spacer, costimulating domain, and an antibody. Antibodies cause immunogenicity; therefore, VHH is a good replacement for ScFv in chimeric receptors. Since peptide sequences have an influence on chimeric receptors, the effect of peptide domains on each other's conformation were investigated. CD3Zeta, CD28, VHH and CD8α, and FcgIIα are used as signaling moieties, costimulating domain, antibody, and spacers, respectively. To investigate the influence of the ligation of spacers on the conformational structure of VHH, models of VHH were constructed. Molecular dynamics simulation was run to study the influence of the presence of spacers on the conformational changes in the binding sites of VHH. Root mean square deviation and root mean square fluctuation of critical segments in the binding site showed no noticeable differences with those in the native VHH. Results from molecular docking revealed that the presence of spacer FcgIIα causes an increasing effect on VHH with MUC1 interaction. Each of the constructs was transformed into the Jurkat E6.1. Expression analysis and evaluation of their functions were examined. The results showed good expression and function.

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Use of multiple picosecond high-mass molecular dynamics simulations to predict crystallographic B-factors of folded globular proteins

10.1101/052126 ◽

2016 ◽

Author(s):

Yuan-Ping Pang

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Molecular Dynamics Simulations ◽

Root Mean Square ◽

A Priori ◽

Model Systems ◽

Dynamics Simulation ◽

High Mass ◽

Mean Square ◽

Dynamics Simulations

ABSTRACTPredicting crystallographic B-factors of a protein from a conventional molecular dynamics simulation is challenging in part because the B-factors calculated through sampling the atomic positional fluctuations in a picosecond molecular dynamics simulation are unreliable and the sampling of a longer simulation yields overly large root mean square deviations between calculated and experimental B-factors. This article reports improved B-factor prediction achieved by sampling the atomic positional fluctuations in multiple picosecond molecular dynamics simulations that use uniformly increased atomic masses by 100-fold to increase time resolution. Using the third immunoglobulin-binding domain of protein G, bovine pancreatic trypsin inhibitor, ubiquitin, and lysozyme as model systems, the B-factor root mean square deviations (mean ± standard error) of these proteins were 3.1 ± 0.2–9 ± 1 Å2for Cα and 7.3 ± 0.9–9.6 ± 0.2 Å2for Cγ, when the sampling was done, for each of these proteins, over 20 distinct, independent, and 50-picosecond high-mass molecular dynamics simulations using AMBER forcefield FF12MC or FF14SB. These results suggest that sampling the atomic positional fluctuations in multiple picosecond high-mass molecular dynamics simulations may be conducive toa prioriprediction of crystallographic B-factors of a folded globular protein.

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Identification of Potential SARS-CoV-2 Main Protease and Spike Protein Inhibitors from the Genus Aloe: An In Silico Study for Drug Development

Molecules ◽

10.3390/molecules26061767 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1767

Author(s):

Mohamed E. Abouelela ◽

Hamdy K. Assaf ◽

Reda A. Abdelhamid ◽

Ehab S. Elkhyat ◽

Ahmed M. Sayed ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Drug Development ◽

Root Mean Square ◽

In Silico ◽

Dynamics Simulation ◽

Spike Protein ◽

Energy Calculation ◽

Mean Square ◽

Main Protease

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.

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Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

Molecules ◽

10.3390/molecules26216538 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6538

Author(s):

Md. Mominur Rahman ◽

Md. Junaid ◽

S. M. Zahid Hosen ◽

Mohammad Mostafa ◽

Lei Liu ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Surface Area ◽

Root Mean Square ◽

Selective Inhibition ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Mean Square ◽

Cox 1

Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD50 in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.

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Virtual screening of curcumin analogues as DYRK2 inhibitor: Pharmacophore analysis, molecular docking and dynamics, and ADME prediction

F1000Research ◽

10.12688/f1000research.28040.1 ◽

2021 ◽

Vol 10 ◽

pp. 394

Author(s):

La Ode Aman ◽

Rahmana Emran Kartasasmita ◽

Daryono Hadi Tjahjono

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Pharmacophore Model ◽

Binding Pocket ◽

26S Proteasome ◽

Dynamics Simulation ◽

Pharmacophore Modelling ◽

Curcumin Analogues ◽

Adme Prediction ◽

Pharmacokinetic Properties

Background: Curcumin reduces the proliferation of cancer cells through inhibition of the DYRK2 enzyme, which is a positive regulator of the 26S proteasome. Methods: In the present work, curcumin analogues have been screened from the MolPort database using a pharmacophore model that comprised a ligand-based approach. The result of the screening was then evaluated by molecular docking and molecular dynamics based on binding the free energy of the interaction between each compound with the binding pocket of DYRK2. The hit compounds were then confirmed by absorption, distribution, metabolism, and excretion (ADME) prediction. Results: Screening of 7.4 million molecules from the MolPort database afforded six selected hit compounds. By considering the ADME prediction, three prospective curcumin analogues have been selected. These are: 2‐[2‐(1‐methylpyrazol‐4‐yl)ethyl]‐1H,5H,6H,7H,8H‐imidazo[4,5‐c]azepin‐4‐one (Molport-035-369-361), methyl 4‐(3‐hydroxy‐1,2‐oxazol‐5‐yl)piperidine‐1‐carboxylate (Molport-000-004-273) and (1S)‐1‐[5‐(furan‐3‐carbonyl)‐4H,6H,7H‐pyrazolo[1,5‐a]pyrazin‐2‐yl]ethanol (MolPort-035-585-822). Conclusion: Pharmacophore modelling, combined with molecular docking and molecular dynamics simulation, as well as ADME prediction were successfully applied to screen curcumin analogues from the MolPort database as DYRK2 inhibitors. All selected compounds that have better predicted pharmacokinetic properties than that of curcumin are considered for further study.

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