scholarly journals Design of Potential SARS-CoV-2 Inhibitor

2020 ◽  
Vol 5 (9) ◽  
pp. 1043-1048
Author(s):  
F. J. Amaku ◽  
I. E. Otuokere ◽  
K. K. Igwe ◽  
O. V. Ikpeazu
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Drug Interaction ◽  
Virtual Screening ◽  
Computational Study ◽  
Enzymatic Reaction ◽  
Target Protein ◽  
Web Servers ◽  
Zinc Database ◽  
Online Web

This computational study comprises of pharmacophore-base virtual screening of the ZINC database, molecular docking of predicted ligands (pharmacophore agent) against the target protein, SARS-CoV-2 (PDB ID: 5r7y) and the prediction of ADMET descriptors using Swiss ADME and PROTOX-II online web servers.  Meanwhile,  remdesivir, ZINC72392503, ZINC72809903, ZINC06560017, ZINC76101700, ZINC88423098 and ZINC91600695 had a docking scores of -2.0 Kcal/mol, -6.7 Kcal/mol, -6.4 Kcal/mol, -6.0 Kcal/mol, -6.0 Kcal/mol, -6.0 Kcal/mol and-6.0 Kcal/mol respectively.  Meanwhile, ZINC72392503 was selected as the lead molecule and was observed to interact with LUE 27, THR 25, CYS 145, THR 26, SER 46, GLY 143, ASN 142, HIS 163, HIS 41, MET 165, GLU 166, ARG 188, GLN 189, HIS 41, MET 49, SER 46 amino acids.  The ADME descriptor revealed that the lead molecule was soluble, druggable, void of drug-drug interaction that may inhibit essential enzymatic reaction and was noticed to fall into PROTOX-II toxicity class 3.  The lead molecule showed a good affinity for the target protein of SARS-CoV-2, hence, may have a physiological implication that can inhibit a protein responsible for the replication of SARS-CoV-2.

scholarly journals Ligand Based 3D-QSAR Pharmacophore, Molecular Docking and Adme to Identify Potential Fibroblast Growth Factor Receptor 1 Inhibitors 

2020 ◽  
Author(s):  
Zizhong Tang ◽  
Lu Huang ◽  
Xiaoli Fu ◽  
Haoxiang Wang ◽  
Biao Tang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Growth Factor Receptor ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Drug Carriers ◽  
Therapeutic Effects ◽  
Lipinski’S Rule ◽  
Discovery Studio ◽  
Zinc Database

Abstract The FGF/FGFR system may affect tumor cells and stromal microenvironment through autocrine and paracrine stimulation, thereby significantly promoting oncogene transformation and tumor growth. Abnormal expression of FGFR1 in cells is considered to be the main cause of tumorigenesis and a potential target for the treatment of cancer. In this study, a combination of structure-based drug carriers and molecular docking-based virtual screening was used to screen new potential FGFR1 inhibitors. Twenty-one known inhibitors were collected as training sets to establish a 3D-QSAR pharmacophore model, and cost analysis, test set validation, and Fischer randomization test were used to validate the efficiency of the pharmacophore model. In Accelrys Discovery Studio 2016, the zinc database was filtered by Lipinski's Rule of Five and SMART's filtration. Then, Hypo01 was used for virtual screening of ZINC database. Compounds with predicted activity values less than 1 μM were molecularly docked with FGFR1 protein crystals, the docking results were observed, and the interaction between compounds and targets was studied. The absorption, distribution, metabolism and excretion (ADME) and toxicity of potential inhibitors were studied, and a compound with new structural scaffolds were obtained. It could be further studied to explore their better therapeutic effects.

scholarly journals Identification of Potential Inhibitors of 3CL Protease of SARS-CoV-2 From ZINC Database by Molecular Docking-Based Virtual Screening

2020 ◽  
Vol 7 ◽  
Author(s):  
Ashraf Ahmed Ali Abdusalam ◽  
Vikneswaran Murugaiyah
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Binding Pocket ◽  
Effective Vaccine ◽  
Autodock Vina ◽  
Zinc Database ◽  
Docking Approach ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
3Cl Protease

The rapid outbreak of Coronavirus Disease 2019 (COVID-19) that was first identified in Wuhan, China is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3CL protease (3CLpro) is the main protease of the SARS-CoV-2, which is responsible for the viral replication and therefore considered as an attractive drug target since to date there is no specific and effective vaccine available against this virus. In this paper, we reported molecular docking-based virtual screening (VS) of 2000 compounds obtained from the ZINC database and 10 FDA-approved (antiviral and anti-malaria) on 3CLpro using AutoDock Vina to find potential inhibitors. The screening results showed that the top four compounds, namely ZINC32960814, ZINC12006217, ZINC03231196, and ZINC33173588 exhibited high affinity at the 3CLpro binding pocket. Their free energy of binding (FEB) were −12.3, −11.9, −11.7, and −11.2 kcal/mol while AutoDock Vina scores were −12.61, −12.32, −12.01, and -11.92 kcal/mol, respectively. These results were better than the co-crystallized ligand N3, whereby its FEB was −7.5 kcal/mol and FDA-approved drugs. Different but stable interactions were obtained between the four identified compounds with the catalytic dyad residues of the 3CLpro. In conclusion, novel 3CLpro inhibitors from the ZINC database were successfully identified using VS and molecular docking approach, fulfilling the Lipinski rule of five, and having low FEB and functional molecular interactions with the target protein. The findings suggests that the identified compounds may serve as potential leads that act as COVID-19 3CLpro inhibitors, worthy for further evaluation and development.

scholarly journals Computational Study of Novel Natural Inhibitors Targeting 3-Phosphoinositi-Dependent Protein Kinase 1(PDK1)

2021 ◽  
Author(s):  
Sheng Zhong ◽  
Zhen Guo ◽  
Gaojing Dou ◽  
Xiaye Lv ◽  
Xinhui Wang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Protein Kinase ◽  
Virtual Screening ◽  
Binding Affinity ◽  
Natural Environment ◽  
Computational Study ◽  
Dynamics Simulation ◽  
Dependent Protein Kinase ◽  
Lead Compounds ◽  
Dependent Protein

Abstract Objective To screen ideal lead compounds with potential inhibition of 3-phosphoinositi-dependent protein kinase 1 (PDK1) from ZINC15 database, which is beneficial to drug design and improvement.Methods The Discovery Studio 4.5 computer-aided virtual screening technique was used to screen potential inhibitors of PDK1. Libdock was used for virtual screening and scoring of candidate compounds, ADME module was used for physical and chemical properties and toxicity analysis, and CDOCKER module was used for molecular docking analysis. The binding affinity of ligand-PDK1 was studied through molecular docking, and the stability of ligand-PDK1 in the natural environment was analyzed through molecular dynamics simulation.Results Two natural compounds ZINC00000157721 and ZINC000034189841 were screened from ZINC15 database. These two compounds have no CYP2D6 inhibition, easy to pass the blood-brain barrier, no hepatotoxicity, high binding affinity with PDK1, higher stability in the natural environment than positive drug BX-795, and stable existence.Conclusions The results show that ZINC00000157721 and ZINC000034189841 are ideal and safe lead compounds and have a potential inhibitory effect on PDK1. These compounds are safe candidates and may provide the basis and premise for the design and optimization of specific PDK1 inhibitors.

scholarly journals Avoiding the Interaction between S-protein of SARS-CoV-2 and ACE2, to Develop an Adjuvant Antiviral by Molecular Docking

2021 ◽  
Vol 12 (4) ◽  
pp. 5234-5265
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
High Probability ◽  
Specific Treatment ◽  
Specific Region ◽  
Web Servers ◽  
S Protein ◽  
New Drug

The COVID-19 pandemic continues today without specific treatment; different treatments have been proposed during this pandemic. This study proposes to develop a new drug by molecular docking, using a library of compounds, almost 500,000 compounds directed to interact in the region between the amino acids (Lys417, Tyr453, Gly496, Gln498, Thr500, Gly502, and Tyr505) in the RBD in S-protein of SARS-CoV-2, to develop a new adjuvant antiviral against COVID-19. It selected ten compounds by molecular docking with a high probability to interact in the specific region in the RBD of SARS-CoV-2 (Lys417, Tyr453, Gly496, Gln498, Thr500, Gly502, and Tyr505), to reduce the interaction with the ACE2. Also, these compounds have a high probability of being safe in humans, validated by web servers of prediction of ADME and toxicity (PreADMET) to develop a new specific adjuvant antiviral against COVID-19.

scholarly journals Repurposing Hydroxychloroquine as a Model Drug for the Prediction of Potential SARS-CoV-2 Inhibitor

2020 ◽  
Vol 5 (9) ◽  
pp. 1031-1036
Author(s):  
K. K. Igwe ◽  
O. V. Ikpeazu ◽  
F. J. Amaku ◽  
I. E. Otuokere
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Binding Energy ◽  
Virtual Screening ◽  
Docking Studies ◽  
Drug Candidate ◽  
Lead Compound ◽  
Toxicity Prediction ◽  
Zinc Database ◽  
Model Drug

The use of hydroxychloroquine as SARS-CoV-2 inhibitor is currently being reviewed in various clinical trials.  To exhaustively assess the benefit of hydroxychloroquine in the search for SARS-CoV-2 cure, this paper repositioned hydroxychloroquine as a model for virtual screening on the ZINC database.  Molecular docking studies of 5r7y with the retrieved molecules were performed.  The S-score of the predicted compounds were compared with the reference inhibitor (hydroxychloroquine).  After evaluating their binding energy, five compounds (ZINC52939663, ZINC21291670, ZINC12714071, ZINC40089978 and ZINC15963294) were noticed have to highest binding energy with SARS-CoV-2.  The binding scores of the top five ligands were higher than that of the reference molecule.  The pharmacokinetics, toxicity prediction, drug-likeness and global reactivity assessment of ZINC52939663, present the lead compound as a drug candidate with the probable capacity to inhibit SARS-CoV-2.

Rational questing for inhibitors of endothelin converting enzyme-1 from Salvia miltiorrhiza by combining ligand- and structure-based virtual screening

2013 ◽  
Vol 91 (6) ◽  
pp. 448-456 ◽  
Author(s):  
Xing Wang ◽  
Yuhong Xiang ◽  
Zhenzhen Ren ◽  
Yanling Zhang ◽  
Yanjiang Qiao
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Salvia Miltiorrhiza ◽  
Scoring Function ◽  
Pharmacophore Model ◽  
Target Protein ◽  
Binding Modes ◽  
Converting Enzyme ◽  
Endothelin Converting Enzyme ◽  
Pharmacophore Models

In this study, a virtual screening approach based on pharmacophore and molecular docking was proposed to identify endothelin converting enzyme-1 (ECE-1) (EC 3.4.24.71) inhibitors from Salvia miltiorrhiza. First, the pharmacophore models were generated to recognize the common features of the ECE-1 inhibitors. The models were validated by a test database composed by a set of compounds known as ECE-1 inhibitors and nonactive compounds and proven to be successful in discriminating active and inactive inhibitors. Then, the best pharmacophore model was used to screen the compounds from S. miltiorrhiza. Furthermore, the Surflex-Dock procedure was used for molecular docking. All compounds from S. miltiorrhiza were docked into the active site of the target protein. An empirical scoring function was used to evaluate the affinity of the compounds and the target protein. Comparing the virtual screening results based on pharmacophore and molecular docking, respectively, 11 communal compounds with higher QFIT and docking score were hit, and the activity of some compounds was validated in the literature. The binding modes between these compounds and the ECE-1 binding site were predicted and used to identify the key interactions that contribute to the inhibitory activity of ECE-1 activity. The results show that the two methods have good consistency and can be validated and supplemented with each other.

Discovery of structural prospects of imidazo[1,5-a]pyrazine derivatives as BTK inhibitors against cancer: A computational study

2021 ◽  
Vol 18 ◽  
Author(s):  
Amena Ali ◽  
Abuzer Ali ◽  
Mohamed Jawed Ahsan
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Anticancer Agents ◽  
Oral Absorption ◽  
Computational Study ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Pharmacokinetic Parameters ◽  
Pharmacophore Hypothesis ◽  
Btk Inhibitors

Background: Bruton’s tyrosine kinase (BTK) plays an important role in cell development and proliferation. BTK inhibitors are encouraging novel agents against B-cell malignancies and autoimmune diseases. Although BTK inhibitors have been approved by the FDA, but to lower off-target effects and to reduce emerging resistances, it is necessary to develop novel BTK inhibitors with better outcomes and minimum side effects. Objective: The present study includes pharmacophore hypothesis, 3D QSAR, virtual screening, docking, ADME analysis and screening of potential imidazo[1,5-a]pyrazine derivatives as BTK inhibitors. Methods: Generation of pharmacophore hypothesis, virtual screening, 3D QSAR, molecular docking and ADME analysis. Methods: Generation of pharmacophore hypothesis, virtual screening, 3D QSAR, molecular docking and ADME analysis. Results: Pharmacophore study generated 20 pharmacophore hypotheses as BTK inhibitor. The five-point hypothesis DPRRR_1 were selected, consist one hydrogen bond donor, one positive ionic, and three ring aromatic features. 3D QSAR study of the compounds provided the best model with high Q2 (0.8683), R2 (0.983) and R2CV (0.5338) values. The developed pharmacophore model was further taken for screening of ZINC database ligands for evaluation of docking interaction and physiochemical properties. Potent compounds of the series 15, 27, 8n and 38 showed good docking scores -8.567, -7.465, -6.922, -6.137, respectively. Conclusion: All the pharmacokinetic parameters analysed, including human oral absorption of active compounds of the series were found to be within the permissible range. The present geometry and features included in pharmacophore hypothesis can be used for the development of novel BTK inhibitors as anticancer agents.

scholarly journals Computational Screening of FDA Approved Drugs from ZINC Database for Potential Inhibitors of Zika Virus NS2B/NS3 Protease: A Molecular Docking and Dynamics Simulation Study

2021 ◽  
pp. 308-319
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Salam Waheed Ahjel ◽  
Zanan Abdulhameed Odhar
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Zika Virus ◽  
Computational Study ◽  
Dynamics Simulation ◽  
Computational Screening ◽  
Approved Drugs ◽  
Ns3 Protease ◽  
Fda Approved Drugs ◽  
Molecular Docking And Dynamics

Zika virus is a mosquito borne pathogen with a single strand RNA genome. Human infection with this virus is usually asymptomatic, however outbreaks reported in both Pacific region and Latin America have been associated with increase in frequency of microcephaly in newborns and fetuses of infected mothers. Also, the incidence of Guillain-Barré syndrome had also increased among adults with Zika virus infection. Currently, neither vaccine nor antiviral drug has been developed against Zika virus. Structure based virtual screening can be employed, through drug repurposing strategy, to accelerate the identification of potential anti-Zika virus candidates. As such, virtual screening of approved drugs against Zika virus NS2B/NS3 protease can help to recognize new hits capable of hindering viral ability to replicate and evade immune system of the host. In this computational study, we have screened 1615 FDA approved drugs against NS2B/NS3 protease enzyme of Zika virus by using both molecular docking and dynamics simulation. Our virtual screening results indicate that the anti-muscarinic agent Darifenacin and the anti-diarrheal agent Loperamide may have a promising capacity to inhibit Zika virus NS2B/NS3 protease. According to molecular docking and dynamics simulation, these two approved drugs have good binding capacity to NS2B/NS3 as reported by docking energy of binding and MM-PBSA binding energy. In addition, both Darifenacin and Loperamide were able to maintain close proximity to protease crystal throughout simulation period. However, invitro evaluation of these two drugs against Zika virus NS2B/NS3 protease is required to confirm these computational results.

Dose COVID-19 Uncovered a New Feature of Metronidazole Drug?

2020 ◽  
Author(s):  
Mohammad Seyedhamzeh ◽  
Bahareh Farasati Far ◽  
Mehdi Shafiee Ardestani ◽  
Shahrzad Javanshir ◽  
Fatemeh Aliabadi ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Virtual Screening ◽  
Active Sites ◽  
Initial Plasma ◽  
New Feature ◽  
Metronidazole Benzoate ◽  
Global Health Problem ◽  
A Current ◽  
Pro Inflammatory Cytokines

Studies of coronavirus disease 2019 (COVID-19) as a current global health problem shown the initial plasma levels of most pro-inflammatory cytokines increased during the infection, which leads to patient countless complications. Previous studies also demonstrated that the metronidazole (MTZ) administration reduced related cytokines and improved treatment in patients. However, the effect of this drug on cytokines has not been determined. In the present study, the interaction of MTZ with cytokines was investigated using molecular docking as one of the principal methods in drug discovery and design. According to the obtained results, the IL12-metronidazole complex is more stable than other cytokines, and an increase in the surface and volume leads to prevent to bind to receptors. Moreover, ligand-based virtual screening of several libraries showed metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5- nitroimidazol-2-yl]-N-methylmethanimine oxide, acyclovir, and tetrahydrobiopterin (THB or BH4) like MTZ by changing the surface and volume prevents binding IL-12 to the receptor. Finally, the inhibition of the active sites of IL-12 occurred by modifying the position of the methyl and hydroxyl functional groups in MTZ. <br>

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