scholarly journals Screening for a Potential Therapeutic Agent from the Herbal Formula in the 4th Edition of the Chinese National Guidelines for the Initial-Stage Management of COVID-19 via Molecular Docking

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Yue Sun ◽  
Angela Wei Hong Yang ◽  
Andrew Hung ◽  
George Binh Lenon
Keyword(s):  
Molecular Docking ◽  
Therapeutic Agent ◽  
Chemical Compounds ◽  
Pharmacokinetic Property ◽  
Herbal Formula ◽  
Stage Management ◽  
National Guidelines ◽  
Initial Stage ◽  
Pharmacokinetic Properties ◽  
Atractylenolide Iii

Background. COVID-19 caused by SARS-CoV-2 infection has been spreading through many countries since the end of 2019. The 4th edition of the national guidelines for the management of COVID-19 provides an herbal formula with 9 herbs for its management. Aim of Study. We aimed to predict the mechanism of binding of SARS-CoV-2 and SARS-CoV spike glycoproteins with angiotensin-converting enzyme 2 (ACE2) to provide a molecular-level explanation of the higher pathogenicity of SARS-CoV-2 and to identify protein sites which may be targeted by therapeutic agents to disrupt virus-host interactions. Subsequently, we aimed to investigate the formula for the initial-stage management to identify a therapeutic agent with the most likely potential to become pharmaceutical candidate for the management of this disease. Materials and Methods. GenBank and SWISS-MODEL were applied for model creation. ClusPro was used for protein-protein docking. PDBePISA was applied for identification of possible binding sites. TCMSP was employed for identification of the chemical compounds. AutoDock Vina together with PyRx was used for the prediction and evaluation of binding pose and affinity to ACE2. SwissADME and PreADME were applied to screening and prediction of the pharmacokinetic properties of the identified chemical compounds. PyMOL was used to visualise the structural models of SARS-CoV-2 and SARS-CoV spike glycoproteins complexed to ACE2 and to examine their interactions. Results. SARS-CoV-2 had two chains (labelled chains B and C) which were predicted to bind with ACE2. In comparison, the SARS-CoV had only one chain (labelled chain C) predicted to bind with ACE2. The spike glycoproteins of both viruses were predicted to bind with ACE2 via position 487. Molecular docking screening and pharmacokinetic property prediction of the herbal compounds indicated that atractylenolide III (−9.1 kcal/mol) from Atractylodes lancea (Thunb.) Dc. (Cangzhu) may be a candidate therapeutic agent for initial-stage management. Conclusions. Atractylenolide III is predicted to have a strong binding affinity with ACE2 and eligible pharmacokinetic properties, anti-inflammatory effects and antiviral effects in in vitro study, and high distribution on the lungs in in vivo study.

Homologation: A Versatile Molecular Modification Strategy to Drug Discovery

2019 ◽  
Vol 19 (19) ◽  
pp. 1734-1750 ◽  
Author(s):  
Lídia M. Lima ◽  
Marina A. Alves ◽  
Daniel N. do Amaral
Keyword(s):  
Protein Structure ◽  
Homologous Series ◽  
Molecular Conformation ◽  
Chemical Properties ◽  
Lead Optimization ◽  
Pharmacokinetic Property ◽  
Molecular Modification ◽  
Physico Chemical ◽  
Pharmacokinetic Properties ◽  
Lead Identification

Homologation is a concept introduced by Gerhard in 1853 to describe a homologous series in organic chemistry. Since then, the concept has been adapted and used in medicinal chemistry as one of the most important strategies for molecular modification. The homologation types, their influence on physico-chemical properties and molecular conformation are presented and discussed. Its application in lead-identification and lead optimization steps, as well as its impact on pharmacodynamics/pharmacokinetic properties and on protein structure is highlighted from selected examples. <p> • Homologation: definition and types <p> • Homologous series in nature <p> • Comparative physico-chemical and conformational properties <p> • Application in lead-identification and lead-optimization <p> • Impact on pharmacodynamic property <p> • Impact on pharmacokinetic property <p> • Impact on protein structure <p> • Concluding remarks <p> • Acknowledgment <p> • References

scholarly journals Preclinical Pharmacokinetics of Scoparone, Geniposide and Rhein in an Herbal Medicine Using a Validated LC-MS/MS Method

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2716 ◽  
Author(s):  
Tun-Pin Hsueh ◽  
Tung-Hu Tsai
Keyword(s):  
Bioactive Compounds ◽  
Pharmacokinetic Study ◽  
High Performance ◽  
Low Dose ◽  
Rat Plasma ◽  
Herbal Formula ◽  
Preclinical Pharmacokinetics ◽  
Pharmacokinetic Properties ◽  
Liquid Chromatography Tandem Mass

The herbal formula Yin-Chen-Hao-Tang has been reported to have anti-fibrosis properties. The aim of this study was to reveal the pharmacokinetic characteristics of bioactive compounds in this herbal formula. A new high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of scoparone, geniposide and rhein in rat plasma. A pharmaceutical herbal powder was administered to rats at doses of 1 g/kg and 3 g/kg orally. The method showed excellent linearity (r2 > 0.999) and validation was successfully conducted for the pharmacokinetic study. The results show that the Cmax values and areas under the curve of scoparone, geniposide and rhein were higher and not proportional to the dose in rat plasma, while the Tmax and half-life values were consistent in the group that received 1 g/kg. The clearance of the higher dose (3 g/kg) did not decrease proportionally to that of the low dose. The results showed the nonlinear pharmacokinetic properties of scoparone, geniposide and rhein in Yin-Chen-Hao-Tang that suggested possible accumulation of bioactive compounds through oral administration. This pharmacokinetic study reveals that an increased dose of this herbal formula would largely increase the maximum concentration and bioavailability of scoparone, geniposide and rhein.

Assessing the Prediction Quality of the Anti-SARS-CoV-2 Activity Using the D3Targets-2019-nCoV Web Service

2020 ◽  
Vol 3 (4) ◽  
pp. e00140
Author(s):  
N.S. Ionov ◽  
P.V. Pogodin ◽  
V.V. Poroikov
Keyword(s):  
Molecular Docking ◽  
Web Service ◽  
Scoring Function ◽  
Chemical Compounds ◽  
Structural Similarity ◽  
Similarity Score ◽  
Test Set ◽  
Target Proteins ◽  
Similarity Assessment

The D3Targets-2019-nCoV web service predicting the interaction of chemical compounds with SARS-CoV-2 virus proteins and human proteins involved in the pathogenesis of COVID-19 by structural similarity and molecular docking was evaluated. The quality of the prediction was assessed as a balanced accuracy, which was calculated based on the results of the prediction for the structures of chemical compounds from the test set we compiled. The test set consisted of 35 active and 59 inactive molecules, including compounds with the experimetnaly confirmed absence of activity against the selected targets and compounds active against SARS-CoV-2 targets, not presented in the CoViLigands database. The authors of the analyzed web service did not indicate the thresholds for the values of the similarity score and the docking scoring function, using which it would be possible to reliably divide the compounds into active and inactive with respect to target proteins. Therefore, we assessed the balanced accuracy of the predictive methods D3Targets-2019-nCoV at various thresholds for cutting off active substances from inactive ones. Using our test set it was found that the highest value of balanced accuracy (0.59) was achieved when choosing active molecules based on the results of 2D similarity assessment (cutoff threshold was 46%). Assessment of 3D similarity did not allow achieving balanced accuracy values exceeding 0.5. It is shown that using the 2Dх3D integral similarity assessment recommended by the authors, the maximum value of the balanced accuracy 0.57 was achieved at a threshold of 31%. The calculated balanced accuracy for molecular docking results does not exceed 0.51. On the case study for the tideglusib, it was shown that the values of the scoring function for two target proteins, the activity against which was confirmed in the experiment (3CLpro and GSK3B), do not differ significantly from the values of the scoring function for the remaining 44 targets were not confirmed.

scholarly journals How can SHAP values help to shape metabolic stability of chemical compounds?

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Agnieszka Wojtuch ◽  
Rafał Jankowski ◽  
Sabina Podlewska
Keyword(s):  
Web Service ◽  
Chemical Compounds ◽  
Structural Features ◽  
Metabolic Stability ◽  
Structural Modifications ◽  
Pharmacokinetic Properties ◽  
Biological Target ◽  
Future Drug ◽  
Living Organisms ◽  
Great Complexity

Abstract Background Computational methods support nowadays each stage of drug design campaigns. They assist not only in the process of identification of new active compounds towards particular biological target, but also help in the evaluation and optimization of their physicochemical and pharmacokinetic properties. Such features are not less important in terms of the possible turn of a compound into a future drug than its desired affinity profile towards considered proteins. In the study, we focus on metabolic stability, which determines the time that the compound can act in the organism and play its role as a drug. Due to great complexity of xenobiotic transformation pathways in the living organisms, evaluation and optimization of metabolic stability remains a big challenge. Results Here, we present a novel methodology for the evaluation and analysis of structural features influencing metabolic stability. To this end, we use a well-established explainability method called SHAP. We built several predictive models and analyse their predictions with the SHAP values to reveal how particular compound substructures influence the model’s prediction. The method can be widely applied by users thanks to the web service, which accompanies the article. It allows a detailed analysis of SHAP values obtained for compounds from the ChEMBL database, as well as their determination and analysis for any compound submitted by a user. Moreover, the service enables manual analysis of the possible structural modifications via the provision of analogous analysis for the most similar compound from the ChEMBL dataset. Conclusions To our knowledge, this is the first attempt to employ SHAP to reveal which substructural features are utilized by machine learning models when evaluating compound metabolic stability. The accompanying web service for metabolic stability evaluation can be of great help for medicinal chemists. Its significant usefulness is related not only to the possibility of assessing compound stability, but also to the provision of information about substructures influencing this parameter. It can assist in the design of new ligands with improved metabolic stability, helping in the detection of privileged and unfavourable chemical moieties during stability optimization. The tool is available at https://metstab-shap.matinf.uj.edu.pl/.

scholarly journals In silico identification of novel chemical compounds with anti-TB potential for the inhibition of InhA and EthR from Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Sajal Kumar Halder ◽  
Fatiha Elma
Keyword(s):  
Molecular Dynamics ◽  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Chemical Compounds ◽  
Dynamics Simulation ◽  
Health Concern ◽  
Radius Of Gyration

ABSTRACTTuberculosis (TB) continuously pose a major public health concern around the globe, with a mounting death toll of approximately 1.4 million in 2019. The reduced bioavailability, increased toxicity and resistance of several first-line and second-line anti-TB drugs such as isoniazid, ethionamide have necessitated the search for new medications. In this research, we have identified several novel chemical compounds with anti-TB properties using various computational tools like molecular docking analysis, drug-likeness evaluation, ADMET profiling, P450 site of metabolism prediction and molecular dynamics simulation study. This study involves fifty drug-like compounds with antibacterial activity that inhibit InhA and EthR involved in the synthesis of one of the major lipid components, mycolic acid, which is crucial for the viability of Mycobacterium tuberculosis. Among these fifty compounds, 3-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-N-(2-methylphenyl) piperidine-1-carboxamide (C22) and 5-(4-Ethyl-phenyl)-2-(1H-tetrazol-5-ylmethyl)-2H-tetrazole (C29) were found to pass the two-step molecular docking, P450 site of metabolism prediction and pharmacokinetics filtering analysis successfully. Their binding stability for target proteins have been evaluated through RMSD, RMSF, Radius of gyration analysis from 10 ns Molecular Dynamics Simulation (MDS) run. Our identified drugs could be a capable therapeutic for Tuberculosis drug discovery, having said that more in vitro and in vivo testing is required to justify their potential as novel drug and mode of action.

scholarly journals Design of more potent quinazoline derivatives as EGFRWT inhibitors for the treatment of NSCLC: a computational approach

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Muhammad Tukur Ibrahim ◽  
Adamu Uzairu ◽  
Sani Uba ◽  
Gideon Adamu Shallangwa
Keyword(s):  
Lung Cancer ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Positive Control ◽  
Computational Approach ◽  
Tyrosine Kinase Receptor ◽  
Binding Affinities ◽  
Binding Interaction ◽  
Pharmacokinetic Properties ◽  
Inhibitory Activities

Abstract Background Lung cancer remains the leading and deadly type of cancer worldwide. It was estimated to account for about 25% of the 7 million people that died as a result of cancer-related issues/mortality every year in the world. Non-small cell lung cancer (NSCLC) is the lethal/deadly class of lung cancer with nearly 1.5 million reported cases and less than 20% survival rate. Therefore, it becomes necessary to explore more effective NSCLC drugs. Result A computational approach was employed here to design ten new EGFRWT inhibitors using compound 18 as a template for the design identified with the best binding affinity and good pharmacokinetic properties previously reported in our work. The modeled inhibitory activities of these newly designed EGFRWT inhibitors (range from 7.746966 to 11.09261) were better than that of the hit compound with pIC50 of 7.5639 and gefitinib the positive control with pIC50 of 5.879426. The ligand-binding interaction between these newly designed EGFRWT inhibitors and the EGFR tyrosine kinase receptor as shown in Table 3 was investigated and elucidated using molecular docking protocol. Based on the molecular docking results, the binding affinities of these newly designed EGFRWT inhibitors were found to be between − 8.8 and − 9.5 kcal/mol. The designed compound SFD10 has the highest binding affinity of − 9.5 kcal/mol followed by compound SFD8 (with a binding affinity of − 9.3 kcal/mol), then by compound SFD9 and 4 (each with a binding affinity of − 9.3 kcal/mol). None of them was found to have more than one violation of the filtering criterion used in this study thereby showing good ADMET properties. Conclusion The modeled inhibitory activities and binding affinities of these newly designed EGFRWT inhibitors were found to be higher than that of the template compound and the control (gefitinib) used in this research. They were also seen to be non-toxic with good pharmacokinetic properties.

scholarly journals PREDICTION OF ANTI-ALZHEIMER’S ACTIVITY OF FLAVONOIDS TARGETING CD33 THROUGH IN-SILICO APPROACH

2021 ◽  
pp. 64-66
Author(s):  
AKILA S. ◽  
MALAR VIZHI S. ◽  
VIJAYALAKSHMI P. ◽  
CLARA MARY A. ◽  
RAJALAKSHMI M.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Social Care ◽  
Docking Studies ◽  
Brain Disorder ◽  
Drug Candidates ◽  
Health And Social Care ◽  
Pharmacokinetic Properties ◽  
Care Systems

Objective: Alzheimer's disease (AD) is a progressive, fatal brain disorder that would be putting a growing strain on health and social care systems. Present anti-AD agents are limited in their application due to their adverse effects, toxicity, and limited targets in AD pathology. As a result, it is important to develop an AD-fighting compound. Some flavonoids (such as kaempferol, myricetin, quercetin, and syringetin) have been shown to be effective in the treatment of Alzheimer's disease. Methods: We chose 284 flavonoids from the NPACT database for molecular docking studies in order to examine their binding interactions with the Alzheimer target protein CD33. Results: These compounds exhibited significant docking interactions with a variety of targets implicated in the pathogenesis of AD. We chose the top three compounds (Rutin, Morin, and,4,4'-Trihydroxydihydrochalcone) based on the scoring parameter. Conclusion: These compounds exhibited favorable pharmacokinetic properties, indicating that they could be attractive drug candidates for the treatment of Alzheimer's disease.

scholarly journals Molecular docking and network connections of active compounds from the classical herbal formula Ding Chuan Tang

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8685
Author(s):  
Allison Clyne ◽  
Liping Yang ◽  
Ming Yang ◽  
Brian May ◽  
Angela Wei Hong Yang
Keyword(s):  
Molecular Docking ◽  
Song Dynasty ◽  
Network Pharmacology ◽  
Herbal Formula ◽  
Protein Targets ◽  
The Song Dynasty ◽  
Network Connections ◽  
Asthma Drug ◽  
Cellular Pathways ◽  
Disease Pathways

Background Ding Chuan Tang (DCT), a traditional Chinese herbal formula, has been consistently prescribed for the therapeutic management of wheezing and asthma-related indications since the Song Dynasty (960–1279 AD). This study aimed to identify molecular network pharmacology connections to understand the biological asthma-linked mechanisms of action of DCT and potentially identify novel avenues for asthma drug development. Methods Employing molecular docking (AutoDock Vina) and computational analysis (Cytoscape 3.6.0) strategies for DCT compounds permitted examination of docking connections for proteins that were targets of DCT compounds and asthma genes. These identified protein targets were further analyzed to establish and interpret network connections associated with asthma disease pathways. Results A total of 396 DCT compounds and 234 asthma genes were identified through database search. Computational molecular docking of DCT compounds identified five proteins (ESR1, KDR, LTA4H, PDE4D and PPARG) mutually targeted by asthma genes and DCT compounds and 155 docking connections associated with cellular pathways involved in the biological mechanisms of asthma. Conclusions DCT compounds directly target biological pathways connected with the pathogenesis of asthma including inflammatory and metabolic signaling pathways.

scholarly journals Molecular Docking, Pharmacokinetic Properties and  Toxicity  Studies of  Novel Folate Conjugated To α-Tocopherol via Peptide Bond

2021 ◽  
Author(s):  
Shams H. Abdel-Hafez ◽  
Adil A. Gobouri ◽  
Anber. F. Mohammed ◽  
Mostafa A. Hussein
Keyword(s):  
Molecular Docking ◽  
Folic Acid ◽  
Anticancer Agents ◽  
Folate Receptor ◽  
Peptide Bond ◽  
Docking Study ◽  
Proton Nuclear Magnetic Resonance ◽  
Molecular Docking Study ◽  
Pharmacokinetic Properties ◽  
Human Folate Receptor

Abstract A novel folate conjugated to α-tocopherol (VAF) via peptide bond was Successfully synthesized by using three components vitamin e (α-tocopherol), chloro acetamide and folic acid under mild and simple conditions. The new synthesized compound was characterized by proton nuclear magnetic resonance 1H NMR, 13H NMR and Fourier transform infrared (FT-IR) analysis. A molecular docking study for targeted compound (VAF ) was performed and showed growth-inhibitory activity towards the human folate receptor alpha (FRα) that may affectively the folate uptake by cancer cells. Further, The predicted pharmacokinetic properties and toxicity of the compound (VAF) and folic acid (F) were determined using a statistical analysis (ADMET). It was suggested that pharmacokinetic properties of compound (VAF) represents a promising drug and used as anticancer agents.

Pyridine and Benzoisothiazole Decorated Vanillin Chalcones: Synthesis, Antimicrobial, Antioxidant, Molecular Docking Study and ADMET Properties

2020 ◽  
Vol 17 (5) ◽  
pp. 367-381
Author(s):  
Pintu Pathare ◽  
Sunil Tekale ◽  
Rafique Shaikh ◽  
Manoj Damale ◽  
Jaiprakash Sangshetti ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Docking Study ◽  
Docking Studies ◽  
Pharmacokinetic Parameters ◽  
Molecular Docking Study ◽  
Antimicrobial Drugs ◽  
Discovery Studio ◽  
Pharmacokinetic Properties

Background: The search for new antimicrobial drugs is a never ending task due to microbial resistance to the existing drugs. Antioxidants are essential to prevent free radical reactions which lead to chronic diseases to human kind. Objective: The present studies were aimed to synthesis, characterization, antimicrobial and antioxidant activities of pyridine and benzoisothiazole decorated chalcones. Materials and Methods: FTIR spectra were recorded using KBr pellets on Shimadzu FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded on Bruker 400 MHz spectrometer. Antimicrobial activity of the synthesized chalcones was found to be good against diffenet bacterial and fungal strains. Antioxidant activity was studied in terms of 2,2-diphenyl-1-picrylhydrazyl, hydroxyI and superoxide radical scavenging activities. Molecular docking was studied using Discovery Studio Visualizer Software, version 16 whereas Autodock Vina program was used to predict toxicity profile of the compounds using FAFDrugs2 predictor. Results: The compounds 5c, 5d & 6c showed good antioxidant activities. The insilico molecular docking study supports the experimental results and demonstrated that the chalcones 5d, 6a and 7a are the most active among the synthesized derivatives. Conclusion: Prediction of pharmacokinetic parameters and molecular docking studies suggest that the synthesized chalcones have good pharmacokinetic properties to act as lead molecules in the drug discovery process.

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