Designs, Synthesis, Docking Studies, and Biological Evaluation of Novel Berberine Derivatives Targeting Zika Virus

The World Health Organization has designated Zika virus (ZIKV) as a dangerous, mosquito-borne flaviviral pathogen that was recently found to be responsible for a dramatically increased number of microcephaly cases and other congenital abnormalities in fetuses and newborns. There is neither a vaccine to prevent nor a drug to treat ZIKA virus infections, at the present time. Berberine (BBR) is a promising drug approved by FDA against flaviviral dengue virus, and BBR derivatives are of great interest in antiviral drug development. In this study, we synthesized eight BBR derivatives by introducing benzyl groups at the C-13 position of BBR and converting to respective 8-oxoberberine derivatives, performed molecular docking analysis, and evaluated their anti-Zika virus activity utilizing a cell‐based phenotypic assay. Binding mode analysis, absolute binding free energy calculation, and structure-activity relationship studies of these compounds with ZIKV NS3 receptor were collected. Amongst these studied compounds, compound 4d with a structure of 13-(2,6-difluoro)-benzylberberine showed high binding affinity (docking score of −7.31 kcal/mol) towards ZIKV NS2B-NS3 protease with critical binding formed within the active site. In the cell-based assay, compound 4d displayed the highest antiviral efficacy against ZIKV with a selective index (SI) of 15.3, with 3.7-fold greater than that of berberine. Together, our study suggests that the potential ZIKV NS2B-NS3 protease inhibitor, compound 4d, is the best alternative to BBR and, further, extends an assuring platform for developing antiviral competitive inhibitors against ZIKV infection.

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Discovery and Computational Analyses of Novel Small Molecule Zika Virus Inhibitors

Molecules ◽

10.3390/molecules24081465 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1465 ◽

Cited By ~ 2

Author(s):

Siyu Zhu ◽

Chaozai Zhang ◽

Lina S. Huang ◽

Xing-Quan Zhang ◽

Yan Xu ◽

...

Keyword(s):

Zika Virus ◽

Binding Free Energy ◽

Binding Mode ◽

Mode Analysis ◽

Energy Calculation ◽

Zikv Infection ◽

Docking Approach ◽

Ic50 Values ◽

Mechanistic Basis ◽

Computational Analyses

Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain–Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC50 values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure–activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.

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Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

10.26434/chemrxiv.8398055 ◽

2019 ◽

Author(s):

David Wright ◽

Fouad Husseini ◽

Shunzhou Wan ◽

Christophe Meyer ◽

Herman Van Vlijmen ◽

...

Keyword(s):

Free Energy ◽

Surface Area ◽

Binding Free Energy ◽

Normal Mode Analysis ◽

Binding Mode ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Mode Analysis ◽

Energy Calculation ◽

Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

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Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

10.26434/chemrxiv.8398055.v1 ◽

2019 ◽

Author(s):

David Wright ◽

Fouad Husseini ◽

Shunzhou Wan ◽

Christophe Meyer ◽

Herman Van Vlijmen ◽

...

Keyword(s):

Free Energy ◽

Surface Area ◽

Binding Free Energy ◽

Normal Mode Analysis ◽

Binding Mode ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Mode Analysis ◽

Energy Calculation ◽

Accessible Surface

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Zika Virus Targeting by Screening Inhibitors against NS2B/NS3 Protease

BioMed Research International ◽

10.1155/2019/3947245 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Hani Choudhry ◽

Faisal A. Alzahrani ◽

Mohammed A. Hassan ◽

Asma Alghamdi ◽

Wesam H. Abdulaal ◽

...

Keyword(s):

Zika Virus ◽

Congenital Abnormalities ◽

Antiviral Drug ◽

Docking Studies ◽

Autodock Vina ◽

Drug Candidates ◽

Fitness Score ◽

Chemical Database ◽

Ns3 Protease ◽

Viral Enzyme

Zika flavivirus is suspected to cause Guillain-Barre syndrome in adults and microcephaly, along with other congenital abnormalities in infants. Presently, no vaccines or therapeutics are available. Here, we report novel compounds identified by high-throughput virtual screening of Maybridge chemical database and molecular docking studies. We selected viral enzyme NS2B/NS3 serine protease as the therapeutic target because of its important role in viral replication. We selected seven potential compounds as antiviral drug candidates because of their high GOLD fitness score, high AutoDock Vina score, or X-Score binding energy and analyzed the strength of molecular interactions between the active site amino acids and selected compounds. Our study also provides a foundation for similar studies for the search of novel therapeutics against Zika virus.

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Synthesis, Biological Evaluation and Docking Studies of 1,2,4,5-Tetrasubstituted Imidazoles as Antibacterial Agents: Use of Niobia Supported Heteropoly Tungstate as an Efficient Reusable Catalyst

Asian Journal of Chemistry ◽

10.14233/ajchem.2021.23181 ◽

2021 ◽

Vol 33 (10) ◽

pp. 2423-2429

Author(s):

Aravind Kurnool ◽

Karunasree Merugu ◽

Pachipulusu Shravya ◽

P. Malleswarareddy

Keyword(s):

Antibacterial Activity ◽

Catalytic Activity ◽

Antibacterial Agents ◽

Ammonium Acetate ◽

Reaction Times ◽

Binding Mode ◽

Docking Studies ◽

Biological Evaluation ◽

Reusable Catalyst ◽

Tetrasubstituted Imidazoles

The synthesis of novel 1,2,4,5-tetrasubstituted imidazoles was carried out in a single molecular motif using niobia supported heteropoly tungstate as a mild and efficient reusable catalyst. The condensation of 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehyde, aromatic amine, benzil, ammonium acetate and heteropoly tungstate supported on niobia was achieved under both conventional and non-conventional conditions. The employed protocol provides significant advantages, as it exhibits a remarkable catalytic activity on recovery, excellent yields and excellent reaction efficacy within short reaction times between 1-2 h (conventional) and 1-3 min (microwave radiation). All the obtained compounds were characterized by means of spectral data and elemental analysis. They were also screened for their antibacterial activity. To predict the binding mode of compounds with glutamine-fructose-6-phosphate transaminase (GlcN6P synthase), docking studies were performed.

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in silico Binding Mode Analysis (Molecular Docking Studies) and Absorption, Distribution, Metabolism and Excretion Prediction of Some Novel Inhibitors of Aurora Kinase A in Clinical Trials

Asian Journal of Chemistry ◽

10.14233/ajchem.2014.17175 ◽

2014 ◽

Vol 26 (18) ◽

pp. 6221-6226 ◽

Cited By ~ 2

Author(s):

Pran Kishore Deb ◽

Dina El-Rabie ◽

Ahmad Junaid ◽

Jeyashanthini A/P Nalaiya ◽

Lim Chee Siong ◽

...

Keyword(s):

Clinical Trials ◽

Molecular Docking ◽

In Silico ◽

Aurora Kinase ◽

Binding Mode ◽

Docking Studies ◽

Mode Analysis ◽

Aurora Kinase A ◽

Molecular Docking Studies ◽

Kinase A

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Binding Mode Prediction and Identification of New Lead Compounds from Natural Products as 3-OST Enzyme Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180817666200313105944 ◽

2020 ◽

Vol 17 (9) ◽

pp. 1186-1196

Author(s):

Rui Sousa ◽

Narayana Subbiah Hari Narayana Moorthy ◽

Pedro Alexandrino Fernandes ◽

Maria Joao Ramos ◽

Natércia Fernandes Brás

Keyword(s):

Model Building ◽

Enzyme Inhibitors ◽

Pharmacophore Model ◽

Binding Mode ◽

Docking Studies ◽

Bioactive Molecules ◽

Mode Analysis ◽

Viral Diseases ◽

Interaction Sites ◽

Screening Study

Background and Introduction: The availability of antiviral medicines for the treatment of viral diseases is limited, hence the discovery of novel bioactive molecules is required. The present investigation has been carried out to develop novel 3-O-sulfotransferase enzyme inhibitors to treat viral diseases. Method: Virtual screening study (QSAR, docking and pharmacophore analysis) and binding mode analysis have been performed on a dataset collected from the literature (synthetic and natural compounds). Results: The docking studies showed that Glu184, His186, Lys215 and Lys368 residues established the most important hydrogen bonding with several hit compounds. The QSAR results explained that the presence of electronegative atoms/groups in the aromatic or heteroaromatic rings confer increased activity. Furthermore, the flexibility and the aromatic rings with less polar groups have better activity than the compounds connected to purine rings. Finally, the structurebased pharmacophore studies illustrated that the ligand has many polar interaction sites, and the projected acceptor and donor groups in the molecules make a significant contribution to the pharmacophore model building. Conclusion: These studies identified two compounds, Phomoidride B and Barceloneic acid A, as potential 3-OST inhibitors.

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Recent Advancements in Docking Methodologies

Oncology ◽

10.4018/978-1-5225-0549-5.ch033 ◽

2017 ◽

pp. 848-875

Author(s):

Vijay Kumar Srivastav ◽

Vineet Singh ◽

Meena Tiwari

Keyword(s):

Molecular Docking ◽

Binding Free Energy ◽

Binding Mode ◽

Docking Studies ◽

Protein Docking ◽

Scoring Functions ◽

Discovery Process ◽

Ligand Complex ◽

Small Molecule Databases ◽

Homology Models

Nowadays molecular docking has become an important methodology in CADD (Computer-Aided Drug Design)-assisted drug discovery process. It is an important computational tool widely used to predict binding mode, binding affinity and binding free energy of a protein-ligand complex. The important factors responsible for accurate results in docking studies are correct binding site prediction, use of suitable small-molecule databases, consistent docking pose, high dock score with good MD (Molecular Dynamics), clarity whether the compound is an inhibitor or agonist, etc. However, still there are several limitations which make it difficult to obtain accurate results from docking studies. In this chapter, the main focus is on recent advancements in various aspects of molecular docking such as ligand sampling, protein flexibility, scoring functions, fragment docking, post-processing, docking into homology models and protein-protein docking.

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