scholarly journals Molecular modeling on the identification of potential Janus Kinase 3 (JAK3) inhibitor based on the Indonesian Medicinal Plant Database

2020 ◽  
Vol 52 (3) ◽  
pp. 276-285
Author(s):  
Muhammad Arba ◽  
Sanang Nur Safitri ◽  
Andry Nur Hidayat ◽  
Arry Yanuar ◽  
Muhammad Sulaiman Zubair ◽  
...  
Keyword(s):  
Md Simulation ◽  
Simulation Analysis ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Janus Kinase ◽  
Great Promise ◽  
Energy Calculation ◽  
Jak3 Inhibitor ◽  
Janus Kinase 3

The Janus tyrosine kinases (JAKs) have shown great promise as therapeutic protein targets in the treatment of cancer and inflammation diseases. This study used pharmacophore modeling to identify potential inhibitors of Janus kinase 3 (JAK3). A pharmacophore model was developed based on a known JAK3 inhibitor (1NX) and was employed to search for potential JAK3 inhibitors against Indonesian herbal compounds. Among 28 hit molecules that were identified and subjected to a molecular docking protocol against JAK3, the three compounds that had the highest affinities toward JAK3 were camelliaside B, 3-O-galloylepicatechin-(4beta-6)-epicatechin-3-O-gallate, and mesuaferrone B. These were then each subjected to a 50-ns molecular dynamics (MD) simulation. Analysis of RMSD and RMSF values indicated that the three compounds reached stability during the MD simulation. Interestingly, all three compounds had lower binding energies than 1NX against JAK3, as predicted by the MM-PBSA binding energy calculation.

Pharmacophore modeling and 3D-QSAR studies of 2,4-disubstituted pyrimidine derivatives as Janus kinase 3 inhibitors

2020 ◽  
Vol 19 (01) ◽  
pp. 2050001
Author(s):  
Neetu Agrawal
Keyword(s):  
Statistical Significance ◽  
Three Dimensional ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Janus Kinase ◽  
Hydrogen Bond Donor ◽  
Pyrimidine Derivatives ◽  
Qsar Studies ◽  
Janus Kinase 3

A robust pharmacophore model was developed and the structure-activity relationship was analyzed using 71 pyrimidine derivatives reported for covalent Janus Kinase 3 (JAK3) inhibition. Pharmacophore modeling developed a five featured pharmacophore: one H-bond acceptor, two H-bond donors, one hydrophobic, and one aromatic ring features. The atom-based three-dimensional QSAR models with statistical significance were generated using the training set of 52 compounds. The excellent predictive correlation coefficients were obtained for 3D models determined using a test set of 19 molecules. The generated QSAR model implies that the hydrophobic character is important for the JAK3 inhibitory activity of these compounds. Additionally, electron-withdrawing and hydrogen bond donor groups at specific positions positively contribute to the JAK3 inhibition potency. These results provided essential three-dimensional structural requirements and the crucial binding features of 2,4-disubstituted pyrimidine derivatives, which may direct for the design and discovery of novel potent JAK3 inhibitors.

scholarly journals Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Firoz A. Dain Md Opo ◽  
Mohammed M. Rahman ◽  
Foysal Ahammad ◽  
Istiak Ahmed ◽  
Mohiuddin Ahmed Bhuiyan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Md Simulation ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Drug Candidate ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Apoptosis Process

AbstractX-linked inhibitor of apoptosis protein (XIAP) is a member of inhibitor of apoptosis protein (IAP) family responsible for neutralizing the caspases-3, caspases-7, and caspases-9. Overexpression of the protein decreased the apoptosis process in the cell and resulting development of cancer. Different types of XIAP antagonists are generally used to repair the defective apoptosis process that can eliminate carcinoma from living bodies. The chemically synthesis compounds discovered till now as XIAP inhibitors exhibiting side effects, which is making difficulties during the treatment of chemotherapy. So, the study has design to identifying new natural compounds that are able to induce apoptosis by freeing up caspases and will be low toxic. To identify natural compound, a structure-based pharmacophore model to the protein active site cavity was generated following by virtual screening, molecular docking and molecular dynamics (MD) simulation. Initially, seven hit compounds were retrieved and based on molecular docking approach four compounds has chosen for further evaluation. To confirm stability of the selected drug candidate to the target protein the MD simulation approach were employed, which confirmed stability of the three compounds. Based on the finding, three newly obtained compounds namely Caucasicoside A (ZINC77257307), Polygalaxanthone III (ZINC247950187), and MCULE-9896837409 (ZINC107434573) may serve as lead compounds to fight against the treatment of XIAP related cancer, although further evaluation through wet lab is necessary to measure the efficacy of the compounds.

scholarly journals Virtual Screening, Molecular Docking and Dynamic Simulation of Shikimate Kinase from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Dr. Mustafa Alhaji Isa
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
3D Structure ◽  
Normal Function ◽  
Binding Energies ◽  
Shikimate Kinase ◽  
Lipinski’S Rule

<p>Shikimate kinase (SK) is an enzyme that catalyzes the fifth steps in the shikimate pathway. The enzyme facilitate the transfer of phosphoryl from ATP to shikimate, to produce ADP and shikimate-3-phosphate from <i>Mycobacterium tuberculosis</i> (MTB). The 3D structure of SK bound ligands (4-(2-Hydroxyethyl)-1-Piperazine Ethanesulfonic Acid (EPE)), ADP and metals (Mg2+, Cl- and Pt+) obtained from PDB (PDB ID: 1L4U and resolution 1.8Å). The structural analysis of the SK revealed that it has a substrate or shikimate binding site (Asp34, Arg58, and Lys136) and substrate binding via amide nitrogen (Gly80). It also possessed nucleotide binding region (Gly12─Thr17), the ATP binding site (Arg117 and Arg153) and metallic ion (Mg2+) binding site (Ser16 and Asp32). All these residues mentioned above play an essential role in the catalytic activity of the SK. Therefore inhibition any of these residues serve as a stumbling block for the normal function of the enzyme. A total of eleven thousand three hundred and twenty-three (11323) compounds obtained from two public databases (Zinc Database and PubChem) capable of binding to SK with good binding affinities. These compounds further filtered for Lipinski’s rule of five, drug-likeness, molecular docking analysis, and ADME and toxicity analysis. Three compounds with minimum binding energies─ PubChem15478 (─11.75 kcal/mol), ZINC02838601 (─11.52 kcal/mol), and ZINC11790367 (─9.88 kcal/mol) ─were selected and used for the MD simulation analysis. Also, MD simulation of the SK bound to EPE, ADP, and Mg2+ were carried out to compare their stabilities with the selected protein-ligand complexes. The result showed that the two compounds (ZINC11790367 and PubChem15478) formed stable and rigid complexes comparable to the bound ligand and the cofactors during the 50ns MD simulation. Therefore, it concluded that the above mentioned two compounds capable of inhibiting SK considered as prospective drugs for MTB after successful experimental validation.</p>

Molecular Docking and Dynamic Simulation of UDP-N-Acetylenolpyruvoylglucosamine Reductase (MurB) Obtained from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Mohammed Mustapha Mohammed
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Data Bank ◽  
Binding Energies ◽  
Peptidoglycan Biosynthesis

<p>The UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) catalyze the final steps of the UDP-N-acetylmuramic acid (UDPMurNAc) formation in the peptidoglycan biosynthesis pathway. The absence of this pathway in mammal made it an attractive target for drug development in <i>Mycobacterium tuberculosis</i> (MTB). In this study, the crystal structure of MurB from MTB (PDB Code: 5JZX and resolution of 2.2 Å) bound to FAD and K<sup>+</sup> was obtained from Protein Data Bank (PDB). A total of 2157 compounds with best binding conformations obtained from zinc database through virtual screening. These compounds further screened for drug-likeness, pharmacokinetic properties, physicochemical properties (Lipinski rule of five), and molecular docking analysis to obtained compounds with desirable therapeutic properties and good binding energies against MurB. Seven compounds (7) with minimum binding energies ranged between ─11.80 and ─10.39kcal/mol were selected, lower than the binding energy of FAD (─10.06kcal/mol). Four compounds with best binding energies (ZINC19837204 = ─11.80kcal/mol, ZINC11839554 = ─11.47kcal/mol, ZINC14976552 = ─10.77kcal/mol) and ability to interact with the residues (ZINC12242812 = ─10.39kcal/mol) of the substrate binding site further selected for the molecular dynamic (MD) simulation analysis. The result of the MD simulation showed that all the four ligands formed stable complexes in the binding site of the MurB, during the 50ns MD simulation, when compared with the cofactor (FAD). Therefore, these compounds were proposed to be novel inhibitors of MTB after <i>in vivo</i> and <i>in vitro</i> validation.</p>

scholarly journals Virtual Screening, Molecular Docking and Dynamic Simulation of Shikimate Kinase from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Dr. Mustafa Alhaji Isa
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
3D Structure ◽  
Normal Function ◽  
Binding Energies ◽  
Shikimate Kinase ◽  
Lipinski’S Rule

<p>Shikimate kinase (SK) is an enzyme that catalyzes the fifth steps in the shikimate pathway. The enzyme facilitate the transfer of phosphoryl from ATP to shikimate, to produce ADP and shikimate-3-phosphate from <i>Mycobacterium tuberculosis</i> (MTB). The 3D structure of SK bound ligands (4-(2-Hydroxyethyl)-1-Piperazine Ethanesulfonic Acid (EPE)), ADP and metals (Mg2+, Cl- and Pt+) obtained from PDB (PDB ID: 1L4U and resolution 1.8Å). The structural analysis of the SK revealed that it has a substrate or shikimate binding site (Asp34, Arg58, and Lys136) and substrate binding via amide nitrogen (Gly80). It also possessed nucleotide binding region (Gly12─Thr17), the ATP binding site (Arg117 and Arg153) and metallic ion (Mg2+) binding site (Ser16 and Asp32). All these residues mentioned above play an essential role in the catalytic activity of the SK. Therefore inhibition any of these residues serve as a stumbling block for the normal function of the enzyme. A total of eleven thousand three hundred and twenty-three (11323) compounds obtained from two public databases (Zinc Database and PubChem) capable of binding to SK with good binding affinities. These compounds further filtered for Lipinski’s rule of five, drug-likeness, molecular docking analysis, and ADME and toxicity analysis. Three compounds with minimum binding energies─ PubChem15478 (─11.75 kcal/mol), ZINC02838601 (─11.52 kcal/mol), and ZINC11790367 (─9.88 kcal/mol) ─were selected and used for the MD simulation analysis. Also, MD simulation of the SK bound to EPE, ADP, and Mg2+ were carried out to compare their stabilities with the selected protein-ligand complexes. The result showed that the two compounds (ZINC11790367 and PubChem15478) formed stable and rigid complexes comparable to the bound ligand and the cofactors during the 50ns MD simulation. Therefore, it concluded that the above mentioned two compounds capable of inhibiting SK considered as prospective drugs for MTB after successful experimental validation.</p>

scholarly journals Design of New Quinazoline Derivative as EGFR (Epidermal Growth Factor Receptor) Inhibitor through Molecular Docking and Dynamics Simulation

2020 ◽  
Vol 21 (1) ◽  
pp. 201
Author(s):  
Herlina Rasyid ◽  
Bambang Purwono ◽  
Harno Dwi Pranowo
Keyword(s):  
Molecular Docking ◽  
Growth Factor Receptor ◽  
Pharmacophore Model ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Egfr Inhibitor ◽  
Lead Compound ◽  
Quinazoline Derivative ◽  
Hydrogen Bond Interaction

Erlotinib, Afatinib, and WZ4002 are quinazoline derivative compounds and classified as first, second, and third-generation EGFR inhibitor. All inhibitors have been given directly to cancer patients for many years but find some resistance. These three compounds are candidates as the lead compound in designing a new inhibitor. This work aims to design a new potential quinazoline derivative as an EGFR inhibitor focused on the molecular docking result of the lead compound. The research method was started in building a pharmacophore model of the lead compound then used to design a new potential inhibitor by employing the AutoDock 4.2 program. Molecular dynamics simulation evaluates the interaction of all complexes using the Amber15 program. There are three new potential compounds (A1, B1, and C1) whose hydrogen bond interaction in the main catalytic area (Met769 residue). The Molecular Mechanics Generalized Born Surface Area (MM-GBSA) binding energy calculation shows that B1 and C1 compounds have lower binding energies than erlotinib as a positive control, which indicates that B1 and C1 are potential as EGFR inhibitor.

scholarly journals Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products

Marine Drugs ◽  
2021 ◽  
Vol 20 (1) ◽  
pp. 29
Author(s):  
Lianxiang Luo ◽  
Ai Zhong ◽  
Qu Wang ◽  
Tongyu Zheng
Keyword(s):  
Molecular Dynamics ◽  
Natural Products ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Marine Natural Products ◽  
Md Simulation ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Dynamics Simulation ◽  
Stable Conformation

Background: In the past decade, several antibodies directed against the PD-1/PD-L1 interaction have been approved. However, therapeutic antibodies also exhibit some shortcomings. Using small molecules to regulate the PD-1/PD-L1 pathway may be another way to mobilize the immune system to fight cancer. Method: 52,765 marine natural products were screened against PD-L1(PDBID: 6R3K). To identify natural compounds, a structure-based pharmacophore model was generated, following by virtual screening and molecular docking. Then, the absorption, distribution, metabolism, and excretion (ADME) test was carried out to select the most suitable compounds. Finally, molecular dynamics simulation was also performed to validate the binding property of the top compound. Results: Initially, 13 small marine molecules were screened based on the pharmacophore model. Then, two compounds were selected for further evaluation based on the molecular docking scores. After ADME and toxicity studies, molecule 51320 was selected for further verification. By molecular dynamics analysis, molecule 51320 maintains a stable conformation with the target protein, so it has the chance to become an inhibitor of PD-L1. Conclusions: Through structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET approaches, and molecular dynamics (MD) simulation, the marine natural compound 51320 can be used as a small molecule inhibitor of PD-L1.

scholarly journals Virtual Screening, Molecular Docking and Pharmacophore Modeling of Phytoconstituents of Flavones as Aldose Reductase Inhibitors

2021 ◽  
pp. 94-107
Author(s):  
Jainey P. James ◽  
Asmath Maziyuna Fabin ◽  
Pradija Sasidharan ◽  
Pankaj Kumar
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Aldose Reductase ◽  
Pharmacophore Model ◽  
Polyol Pathway ◽  
Pharmacophore Modeling ◽  
Antidiabetic Activity ◽  
Energy Calculation ◽  
Reductase Inhibitors ◽  
Characteristic Features

Flavones are an important class of naturally occurring heterocycles possessing various pharmacological activities. An in silico approach was carried out where 506 compounds containing flavone ring were utilised as ligand against the target aldose reductase enzyme. Aldose reductase is the rate-limiting enzyme in the polyol pathway, which indirectly causes diabetic complications like diabetic nephropathy and diabetic retinopathy. The flavone containing compounds retrieved from the PubChem were investigated by HTVS (high throughput virtual screening) followed by molecular docking using glide SP and XP docking module in Maestro of Schrodinger software. Among them, the best fifteen compounds were selected for further studies. The binding energy calculation was done using the Prime MM-GBSA module. PASS online prediction tools were used for predicting the antidiabetic activity of the compounds. Also, a pharmacophore model was generated for best interacted fifteen compounds by Phase, which can be used for evaluation of the characteristic features essential for this specific biological activity. The ADMET properties of the compounds were determined using the Qikprop module in the Schrodinger software.

Computational Study on Novel Natural Inhibitors Targeting Janus Kinase 3

2021 ◽  
Author(s):  
Sheng Zhong ◽  
Weihang Li ◽  
Bo Wu ◽  
Yujia Zou ◽  
Hui Li ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Simulation Analysis ◽  
Computational Study ◽  
Target Therapy ◽  
Janus Kinase ◽  
Dynamics Simulation ◽  
Janus Kinase 3 ◽  
Leading Compounds ◽  
Natural Inhibitors

Abstract Objective: The aim of this study is to screen and identify novel leading compounds 5 which can inhibit protein Janus Kinase 3 (JAK3) from a drug library (ZINC database) 6 to provide precise target therapy for lung cancer. 7Methods: A set of computation-aided structural biology methods and chemical virtual 8 screening techniques were carried out to screen novel inhibitor compounds. Libdock 9 scores for potential inhibitors of JAK3 were calculated using fast docking method-10 virtual screening. Next, ADMET properties (absorption, distribution, metabolism, 11 excretion, and toxicity) were conducted to predict their pharmacological characteristics. 12 The binding affinity as well as the interactions between the candidate compounds and 13 JAK3 were calculated and visualized by precise molecular docking algorithm. 14 Ultimately, molecular dynamics simulation (MD) was performed to estimate the 15 stability of the ligand-JAK3 complex under natural environment. 16Results: After screening, two novel natural compounds, ZINC000014952116 and 17 ZINC00000393864, were finally selected as leading compounds from the ZINC15 18 database, which possessed less Ames mutagenicity, rodent carcinogenicity and 19 developmental toxicity potential than other candidate compounds. Additionally, they 20 didn’t inhibit the activity of CYP2D6. Molecular dynamics simulation analysis showed 21 that ZINC000014952116 and ZINC00000393864 could interact with JAK3 steadily, 22 and their ligand-JAK3 complexes could keep stable under natural situation, and act as 23 regulatory role to JAK3. 24Conclusion: This study analyzed that ZINC000014952116 and ZINC00000393864 25 were ideal natural inhibitors targeting JAK3 from the ZINC15 database, which could 26 also provide more options and resources for other cancer chemotherapy.

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