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

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.

scholarly journals Molecular Docking Studies and Comparative Binding Mode Analysis of FDA Approved HIV Protease Inhibitors

2014 ◽  
Vol 26 (18) ◽  
pp. 6227-6232 ◽  
Author(s):  
Pran Kishore Deb ◽  
Ahmad Junaid ◽  
Dina El-Rabie ◽  
Tan Yee Hon ◽  
Elham Mohammadi Nasr ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Mode ◽  
Docking Studies ◽  
Hiv Protease ◽  
Mode Analysis ◽  
Hiv Protease Inhibitors ◽  
Molecular Docking Studies ◽  
Comparative Binding

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

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Cuong Quoc Nguyen ◽  
Thi Hong Minh Nguyen ◽  
Thi Thu Thuy Nguyen ◽  
Thi Buu Hue Bui ◽  
Trong Tuan Nguyen ◽  
...  
Keyword(s):  
Zika Virus ◽  
Binding Free Energy ◽  
Antiviral Drug ◽  
Binding Mode ◽  
Docking Studies ◽  
Biological Evaluation ◽  
World Health ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Ns3 Protease

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.

scholarly journals 3D QSAR Pharmacophore Based Virtual Screening, ADME Analysis and Estimation of MM/GBSA binding Free Energies of Azoles as a Potential Inhibitor of DprE1 for Mycobacterium Tuberculosis

2021 ◽  
Author(s):  
Madhavaram Madhavi ◽  
Nampally Venkatesh ◽  
Tigulla Parthasarathy
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Antitubercular Activity ◽  
Binding Mode ◽  
Mode Analysis ◽  
Cell Wall Biosynthesis ◽  
Qsar Studies ◽  
Pathway Inhibition

Abstract Decaprenylphosphoryl - D – ribose – 2 –epimerase (DprE1) is a promising drug target to identify new anti- TB drugs against drug resistant tuberculosis. DprE1 helps in cell wall biosynthesis through Decaprenyl-phosphoryl d-arabinose pathway. Inhibition of DprE1 results in blocking of cell wall biosynthesis, causing death of mycobacterium tuberculosis. In current studies, a set of thirty triazole molecules having antitubercular activity were selected for pharmacophore 3D QSAR studies. The generated common pharmacophore hypothesis (AHRRR.172) consists of one acceptor (A), one hydrophobic (H), and three aromatic rings (R). The resulted pharmacophore model recorded with good statistical results, R2 = 0.71, Q2 = 0.54 and other parameters F = 45, RMSE = 0.41. This model further investigated to identify pharmacophoric features which are crucial for biological activity. The resultant pharmacophore model was used to screen ZINC chemical database molecules to identify potent lead molecules against DprE1 enzyme. The resultant hit molecules were recorded with dihydroquinonolin 2-one and Pyrazolo [1, 5] pyramidin 5-one scaffold and this information could be helpful to design new potent anti-tuberculosis agent. Further, these molecules along with co-crystal ligand were utilized for the estimation of physicochemical properties and followed by binding mode analysis.

scholarly journals A BATTLE AGAINST AIDS: NEW PYRAZOLE KEY TO AN OLDER LOCK-REVERSE TRANSCRIPTASE

2016 ◽  
Vol 8 (11) ◽  
pp. 75 ◽  
Author(s):  
Sony Jacob K. ◽  
Swastika Ganguly
Keyword(s):  
Molecular Docking ◽  
Oral Absorption ◽  
Binding Mode ◽  
Docking Studies ◽  
Mode Analysis ◽  
Protein Preparation ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Protein Preparation Wizard

Objective: The reason for the failure of most of the anti-HIV drugs are their poor pharmacokinetics, the poor risk to benefit ratio and the drug resistance. With the objective of developing newer pyrazole scaffolds for effective treatment of HIV, binding mode analysis of designing ligands with the HIV-1RT protein and prediction of key ADME and toxicity parameters of the compounds was in an area of interest.Methods: In this study, molecular docking studies and ADME-T studies were carried out in designing of some novel pyrazole analogs. The protein (PDB ID: 1RT2) was prepared using the Protein Preparation Wizard (Schrodinger Glide 5.0). ADME parameters calculated by QikProp 3.0v and toxicity of designed analogs checked by using two different online software’s namely Lazar and protox.Results: Most of the designed pyrazole analogs have good oral absorption as well as good binding affinity towards HIV-1 reverse transcriptase.Conclusion: Finally total 5 analogs (SGS-2, 3, 12, 13 and 14) from the 14 designed leads were found to be best on the basis of molecular docking and ADME-T studies.

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

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>

Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study

2020 ◽  
Vol 22 (9) ◽  
pp. 635-648 ◽  
Author(s):  
Korosh Mashayekh ◽  
Shahrzad Sharifi ◽  
Tahereh Damghani ◽  
Maryam Elyasi ◽  
Mohammad S. Avestan ◽  
...  
Keyword(s):  
Critical Role ◽  
Scientific Work ◽  
Binding Mode ◽  
Docking Studies ◽  
Conformational Space ◽  
Hydrogen Bond Interactions ◽  
Docking Program ◽  
Dynamics Simulations ◽  
Computational Drug Discovery ◽  
Dynamic Ensembles

Background: c-Met kinase plays a critical role in a myriad of human cancers, and a massive scientific work was devoted to design more potent inhibitors. Objective: In this study, 16 molecular dynamics simulations of different complexes of potent c-Met inhibitors with U-shaped binding mode were carried out regarding the dynamic ensembles to design novel potent inhibitors. Methods: A cluster analysis was performed, and the most representative frame of each complex was subjected to the structure-based pharmacophore screening. The GOLD docking program investigated the interaction energy and pattern of output hits from the virtual screening. The most promising hits with the highest scoring values that showed critical interactions with c-Met were presented for ADME/Tox analysis. Results: The screening yielded 45,324 hits that all of them were subjected to the docking studies and 10 of them with the highest-scoring values having diverse structures were presented for ADME/Tox analyses. Conclusion: The results indicated that all the hits shared critical Pi-Pi stacked and hydrogen bond interactions with Tyr1230 and Met1160 respectively.

Arylhydrazono/Aryldiazenyl Pyrazoles: Green One-Pot Solvent-Free Synthesis and Anticancer Evaluation

2020 ◽  
Vol 17 (10) ◽  
pp. 772-778
Author(s):  
Abdulrhman Alsayari ◽  
Abdullatif Bin Muhsinah ◽  
Yahya I. Asiri ◽  
Jaber Abdullah Alshehri ◽  
Yahia N. Mabkhot ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Binding Mode ◽  
Docking Studies ◽  
Solvent Free ◽  
Pyrazole Derivatives ◽  
One Pot ◽  
Solvent Free Conditions ◽  
Hybrid Molecules

The aim of this study was to synthesize and evaluate the biological activity of pyrazole derivatives, in particular, to perform a “greener” one-pot synthesis using a solvent-free method as an alternative strategy for synthesizing hydrazono/diazenyl-pyridine-pyrazole hybrid molecules with potential anticancer activity. Effective treatment for all types of cancers is still a long way in the future due to the severe adverse drug reactions and drug resistance associated with current drugs. Therefore, there is a pressing need to develop safer and more effective anticancer agents. In this context, some hybrid analogues containing the bioactive pharmacophores viz. pyrazole, pyridine, and diazo scaffolds were synthesized by one-pot method. Herein, we describe the expedient synthesis of pyrazoles by a onepot three-component condensation of ethyl acetoacetate/acetylacetone, isoniazid, and arenediazonium salts under solvent-free conditions, and the evaluation of their cytotoxicity using a sulforhodamine B assay on three cancer cell lines. Molecular docking studies employing tyrosine kinase were also carried out to evaluate the binding mode of the pyrazole derivatives under study. 1-(4-Pyridinylcarbonyl)-3- methyl-4-(2-arylhydrazono)-2-pyrazolin-5-ones and [4-(2-aryldiazenyl)-3,5-dimethyl-1H-pyrazol-1- yl]-4-pyridinylmethanones, previously described, were prepared using an improved procedure. Among these ten products, 1-isonicotinoyl-3-methyl-4-[2-(4-nitrophenyl)hydrazono]-2-pyrazolin-5-one (1f) displayed promising anticancer activity against the MCF-7, HepG2 and HCT-116 cell lines, with an IC50 value in the range of 0.2-3.4 μM. In summary, our findings suggest that pyrazoles containing hydrazono/ diazenyl and pyridine pharmacophores constitute promising scaffolds for the development of new anticancer agents.

Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

2019 ◽  
Vol 16 (7) ◽  
pp. 775-784
Author(s):  
Richa Arya ◽  
Satya Prakash Gupta ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medical Condition ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Pyridine Derivative ◽  
Cleavage Enzyme ◽  
Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies

2019 ◽  
Vol 15 (2) ◽  
pp. 257-267 ◽  
Author(s):  
Paritosh Shukla ◽  
Ashok Sharma ◽  
Leena Fageria ◽  
Rajdeep Chowdhury
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
In Silico ◽  
Antimicrobial Agents ◽  
Docking Studies ◽  
Bioactive Molecules ◽  
Microwave Assisted Synthesis ◽  
Binding Affinities ◽  
In Silico Docking

Background: Cancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findings. Conclusion: The paper describes a comprehensive synthesis, in-vitro and docking studies done on new PPZs. The newly synthesized series of spiro and non-spiro PPZs were found to possess antineoplasmic activity as evinced by the studies on hep3b cells. Also, the UV visible absorbance study gave clues to the possible binding of these molecules to the DNA. Docking studies corroborated well with the experimental results. Thus, these new molecules appear to be potential anticancer agents, but further studies are required to substantiate and elaborate on these findings.

Sign in / Sign up

Export Citation Format

Share Document