Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies

EphB3 is a major key player in a variety of cellular activities, including cell migration, proliferation, and apoptosis. However, the exact role of EphB3 in cancer remains ambiguous. Accordingly, new EphB3 inhibitors can increase the understanding of the exact roles of the receptor and may act as promising therapeutic candidates. Herein, a hybrid approach of structure-based design and virtual combinatorial library generated 34 quinazoline sulfonamides as potential selective EphB3 inhibitors. A molecular docking study over EphB3 predicted the binding affinities of the generated library, and the top seven hit compounds (3a and 4a–f), with GlideScore ≥ −6.20 Kcal/mol, were chosen for further MM-GBSA calculations. Out of the seven top hits, compound 4c showed the highest MM-GBSA binding free energy (−74.13 Kcal/mol). To validate these predicted results, compounds 3a and 4a–f were synthesized and characterized using NMR, HRMS, and HPLC. The biological evaluation revealed compound 4c as a potent EphB3 inhibitory lead (IC50 = 1.04 µM). The screening of 4c over a mini-panel of kinases consisting of EGFR, Aurora A, Aurora B, CDK2/cyclin A, EphB1, EphB2, EphB4, ERBB2/HER2, and KDR/VEGFR2, showed a promising selective profile against EphB3 isoform. A dose-dependent assay of compound 4c and a molecular docking study over the different forms of EphB provided insights into the elicited biological activities and highlighted reasonable explanations of the selectivity.

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Synthesis, characterization, in silico molecular docking study and biological evaluation of a 5-(phenylthio) pyrazole based polyhydroquinoline core moiety

New Journal of Chemistry ◽

10.1039/c7nj01962a ◽

2017 ◽

Vol 41 (19) ◽

pp. 10686-10694 ◽

Cited By ~ 6

Author(s):

Nirav H. Sapariya ◽

Beena K. Vaghasiya ◽

Rahul P. Thummar ◽

Ronak D. Kamani ◽

Kirit H. Patel ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Combinatorial Library ◽

Docking Study ◽

Biological Evaluation ◽

Molecular Docking Study ◽

Cyclocondensation Reaction ◽

In Silico Molecular Docking

A combinatorial library of polyhydroquinoline scaffolds is successfully attempted by multicomponent cyclocondensation reaction.

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Potential of Plant Bioactive Compounds as SARS-CoV-2 Main Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study

10.20944/preprints202004.0102.v2 ◽

2020 ◽

Cited By ~ 4

Author(s):

Trina Ekawati Tallei ◽

Sefren Geiner Tumilaar ◽

Nurdjannah Jane Niode ◽

Fatimawali Fatimawali ◽

Billy Johnson Kepel ◽

...

Keyword(s):

Free Energy ◽

Molecular Docking ◽

Bioactive Compounds ◽

Binding Free Energy ◽

Biological Activities ◽

Epigallocatechin Gallate ◽

Docking Study ◽

Molecular Docking Study ◽

Main Protease ◽

Glycoprotein Inhibitors

Background: Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, researchers have been trying to investigate several active compounds found in plants that have the potential to inhibit the proliferation of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of COVID-19. The search for plant-based antivirals against the SARS-CoV-2 is promising, as several plants have been shown to possess antiviral activities against betacoronaviruses (beta-CoVs) Objective: The present study aimed to evaluate bioactive compounds found in plants by using a molecular docking approach to inhibit Main Protease (Mpro) (PDB code: 6LU7) and Spike (S) Glycoprotein (PDB code: 6VXX) of SARS-CoV-2. Methods: Evaluation was performed on the docking scores calculated using AutoDock Vina as a docking engine. For each compound that was docked, a rule of five was calculated to determine whether a compound with certain pharmacological or biological activities might have chemical and physical properties that would make it an active drug orally in humans. Determination of the docking score was done by selecting the conformation of the ligand that has the lowest binding free energy (best pose). As a comparison, nelfinavir (an antiretroviral drug), chloroquine and hydroxychloroquine sulfate (anti-malarial drugs recommended by the FDA as emergency drugs) were used. Results: The results showed that hesperidine, cannabinoids, pectolinarin, epigallocatechin gallate, and rhoifolin had better poses than nelfinavir, chloroquine and hydroxychloroquine sulfate as spike glycoprotein inhibitors. Hesperidin, rhoifolin, pectolinarin, and cannabinoids had about the same pose as nelfinavir, but were better than chloroquine and hydroxychloroquine sulfate as Mpro inhibitors. These plant compounds have the potential to be developed as specific therapeutic agents against COVID-19. Conclusion: Several natural compounds of plants evaluated in this study showed better binding free energy compared to nelfinavir, chloroquine and hydroxychloroquine sulfate which so far are recommended in the treatment of COVID-19.

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Biological Evaluation and Molecular Docking with In Silico Physicochemical, Pharmacokinetic and Toxicity Prediction of Pyrazolo[1,5-a]pyrimidines

Molecules ◽

10.3390/molecules25061431 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1431 ◽

Cited By ~ 2

Author(s):

Ahmed M. Naglah ◽

Ahmed A. Askar ◽

Ashraf S. Hassan ◽

Tamer K. Khatab ◽

Mohamed A. Al-Omar ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Biological Activities ◽

Antimicrobial Properties ◽

Docking Study ◽

Biological Evaluation ◽

Immunomodulatory Activity ◽

Molecular Docking Study ◽

Lipinski’S Rule

Pyrazolo[1,5-a]pyrimidines 5a–c, 9a–c and 13a–i were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-a]pyrimidines showed that the pyrazolo[1,5-a]pyrimidines (5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h) displayed promising antimicrobial and immunomodulatory activities. Studying the in silico predicted physicochemical, pharmacokinetic, ADMET and drug-likeness properties for the pyrazolo[1,5-a]pyrimidines 5a–c, 9a–c and 13a–i confirmed that most of the compounds (i) were within the range set by Lipinski’s rule of five, (ii) show higher gastrointestinal absorption and inhibition of some CYP isoforms, and (iii) have a carcinogenicity test that was predicted as negative and hERG test that presented medium risk. Moreover, the molecular docking study demonstrated that the compounds 5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h are potent inhibitors of 14-alpha demethylase, transpeptidase and alkaline phosphatase enzymes. This study could be valuable in the discovery of a new series of drugs.

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Potential of Plant Bioactive Compounds as SARS-CoV-2 Main Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study

10.20944/preprints202004.0102.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Trina Ekawati Tallei ◽

Sefren Geiner Tumilaar ◽

Nurdjannah Jane Niode ◽

Fatimawali Fatimawali ◽

Billy Johnson Kepel ◽

...

Keyword(s):

Free Energy ◽

Molecular Docking ◽

Bioactive Compounds ◽

Binding Free Energy ◽

Biological Activities ◽

Epigallocatechin Gallate ◽

Docking Study ◽

Molecular Docking Study ◽

Main Protease ◽

Glycoprotein Inhibitors

Background: Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, researchers have been trying to investigate several active compounds found in plants that have the potential to inhibit the proliferation of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of COVID-19. The search for plant-based antivirals against the SARS-CoV-2 is promising, as several plants have been shown to possess antiviral activities against betacoronaviruses (beta-CoVs) Objective: The present study aimed to evaluate bioactive compounds found in plants by using a molecular docking approach to inhibit Main Protease (Mpro) (PDB code: 6LU7) and Spike (S) Glycoprotein (PDB code: 6VXX) of SARS-CoV-2. Methods: Evaluation was performed on the docking scores calculated using AutoDock Vina as a docking engine. For each compound that was docked, a rule of five was calculated to determine whether a compound with certain pharmacological or biological activities might have chemical and physical properties that would make it an active drug orally in humans. Determination of the docking score was done by selecting the conformation of the ligand that has the lowest binding free energy (best pose). As a comparison, nelfinavir (an antiretroviral drug), chloroquine and hydroxychloroquine sulfate (anti-malarial drugs recommended by the FDA as emergency drugs) were used. Results: The results showed that hesperidine, cannabinoids, pectolinarin, epigallocatechin gallate, and rhoifolin had better poses than nelfinavir, chloroquine and hydroxychloroquine sulfate as spike glycoprotein inhibitors. Hesperidin, rhoifolin, pectolinarin, and cannabinoids had about the same pose as nelfinavir, but were better than chloroquine and hydroxychloroquine sulfate as Mpro/3CLpro inhibitors. These plant compounds have the potential to be developed as specific therapeutic agents against COVID-19. Conclusion: Several natural compounds of plants evaluated in this study showed better binding free energy compared to nelfinavir, chloroquine and hydroxychloroquine sulfate which so far are recommended in the treatment of COVID-19.

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Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

Medicinal Chemistry ◽

10.2174/1573406415666190724142951 ◽

2020 ◽

Vol 16 (7) ◽

pp. 892-902 ◽

Cited By ~ 3

Author(s):

Aida Iraji ◽

Mahsima Khoshneviszadeh ◽

Pegah Bakhshizadeh ◽

Najmeh Edraki ◽

Mehdi Khoshneviszadeh

Keyword(s):

Molecular Docking ◽

Active Site ◽

Competitive Inhibition ◽

Docking Study ◽

Biological Evaluation ◽

Primary Response ◽

Ratio Method ◽

Molecular Docking Study ◽

Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

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