Molecular modeling and docking calculations of 4-acyloxy-biphenyl-4′-N-butylcarbamates as potential inhibitors of human butyrylcholinesterase

2016 ◽  
Vol 94 (1) ◽  
pp. 72-77 ◽  
Author(s):  
Yu-Fang Shen ◽  
Gan-Hong Chen ◽  
Shu-Hsien Lin ◽  
Gialih Lin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Energy ◽  
Linear Correlation ◽  
Kinetic Studies ◽  
Docking Studies ◽  
Binding Energies ◽  
Binding Modes ◽  
Docking Calculations ◽  
Potential Inhibitors

The kinetic studies and drug designs of butyrylcholinesterase play an important role in the development of Alzheimer’s disease therapeutics. In this research, automated docking studies were performed to provide useful insights into butyrylcholinesterase inhibition binding modes with designed 4-acyloxy-biphenyl-4′-N-butylcarbamates (compounds 1–8). Moreover, several significant linear correlations between experimental and calculated docking results are observed. Among compounds 1–7, compound 3, which exhibits the strongest hydrophobicity and has four carbonyl hydrogen bindings, shows the highest binding affinity (Ki = 1.4 μmol/L) with a binding energy of −7.99 kcal/mol. The observed linear correlation of experimental and calculated inhibition constants (Ki) indicates that the molecular docking results are reliable. Moreover, a good linear correlation is observed between calculated binding energies and experimental pKi. The experimental Hansch hydrophobicity constants (π values) are also correlated with the docked binding energy. This study reveals important correlations between butyrylcholinesterase experimental and docking results that contribute to the kinetic based identification of antagonists for the treatment of Alzheimer’s disease. Furthermore, these docked models provide important insights into a potential series of 4,4′-biphenol-based inhibitors of butyrylcholinesterase.

Ajmalicine and its Analogues Against AChE and BuChE for the Management of Alzheimer’s Disease: An In-silico Study

2020 ◽  
Vol 26 (37) ◽  
pp. 4808-4814
Author(s):  
Shu Liu ◽  
Minyan Dang ◽  
Yan Lei ◽  
Syed S. Ahmad ◽  
Mohammad Khalid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Energy ◽  
3D Structure ◽  
Docking Studies ◽  
Kcal Mole ◽  
In Silico Study ◽  
Phytochemical Compounds ◽  
Inhibitory Potential ◽  
Potential Inhibitors

Background: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and non-cognitive functions. Objective: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology. Methods: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using ‘Autodock4.2’. Results: wo phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of -9.02 and -8.89 kcal/mole, respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. Conclusion: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values.

scholarly journals The investigation of 2D monolayers as potential chelation agents in Alzheimer’s disease

2019 ◽  
Author(s):  
Neha Pavuluru ◽  
Xuan Luo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Charge Transfer ◽  
Binding Energy ◽  
Amyloid Beta ◽  
Density Functional ◽  
Density Functional Theory Calculations ◽  
Binding Energies ◽  
Amyloid Beta Protein ◽  
Functional Theory

In this study, we conducted Density Functional Theory calculations comparing the binding energy of the copper- Amyloid-beta complex to the binding energies of potential chelation materials. We used the first-coordination sphere of the truncated high-pH Amyloid-beta protein subject to computational limits. Binding energy and charge transfer calculations were evaluated for copper’s interaction with potential chelators: monolayer boron nitride, monolayer molybdenum disulfide, and monolayer silicene. Silicene produced the highest binding energies to copper, and the evidence of charge transfer between copper and the monolayer proves that there is a strong ionic bond present. Although our three monolayers did not directly present chelation potential, the absolute differences between the binding energies of the silicene binding sites and the Amyloid-beta binding site were minimal proving that further research in silicene chelators may be useful for therapy in Alzheimer’s disease.

scholarly journals Virtual Screening of Curcumin and Its Analogs Against the Spike Surface Glycoprotein of SARS-CoV-2 and SARS-CoV

2020 ◽  
Author(s):  
Ashish Patel ◽  
Malathi Rajendran ◽  
Suresh B Pakala ◽  
Ashish Shah ◽  
Harnisha Patel ◽  
...  
Keyword(s):  
Binding Energy ◽  
Viral Entry ◽  
Curcuma Longa ◽  
Docking Studies ◽  
Binding Energies ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Pharmacokinetic Parameters ◽  
Angiotensin Converting Enzyme 2 ◽  
Potential Inhibitors

COVID-19, a new pandemic caused by SARS-CoV-2, was first identified in 2019 in Wuhan, China. The novel corona virus SARS-CoV-2 and the 2002 SARS-CoV have 74 % identity and use similar mechanisms to gain entry into the cell. Both the viruses enter the host cell by binding of the viral spike glycoprotein to the host receptor, angiotensin converting enzyme 2 (ACE2). Targeting entry of the virus has a better advantage than inhibiting the later stages of the viral life cycle. Potential inhibitors of SARS-CoV and SARS-CoV-2 Spike proteins was determined using molecular docking studies. Curcumin, a naturally occurring phytochemical in Curcuma longa, is known to have broad pharmacological properties. In the present study, curcumin and its derivatives were docked, using Autodock 4.2, onto the 6CRV and 6M0J to study their capability to act as inhibitors of the spike protein and thereby, viral entry. The curcumin and its derivatives displayed binding energies, ΔG, ranging from -14.18 to -4.04 kcal/mol (6CRV) and -10.01 to -5.33 kcal/mol (6M0J). The least binding energy was seen in bis-desmethoxycurcumin with: ΔG = -14.18 kcal/mol (6CRV) and -10.01 kcal/mol (6M0J). A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin and few of its derivatives as SARS-CoV-2 spike protein inhibitors.<br>

Molecular Docking Studies for Protein-Targeted Drug Development in SARS-CoV-2

2021 ◽  
Vol 18 ◽  
Author(s):  
Ahmad Dzulfikri Nurhan ◽  
Maria Apriliani Gani ◽  
Saipul Maulana ◽  
Siswandono Siswandono ◽  
Chrismawan Ardianto ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Docking Studies ◽  
Binding Energies ◽  
Spike Glycoprotein ◽  
Protein Targets ◽  
Lipinski’S Rule ◽  
Global Pandemic ◽  
Potential Inhibitors ◽  
3Cl Protease

Background: The SARS-CoV-2/COVID-19 infection has resulted in a global pandemic and emergency. Currently, there is no therapeutic agent that has been proven to be effective and selective to deal with this pandemic. Objective: In this study, we explored and screened 401 compounds-related viruses that may inhibit one or more of the three protein targets in SARS-CoV-2 (3CL protease, RdRp, and spike glycoprotein) using in-silico approach. Methods: Lipinski's rule of five was used as an initial screening for these compounds. Ligand preparation was carried out using JChem software and Schrödinger's LigPrep module, while protein elucidation used AutoDockTools-1.5.6. Molecular docking was analyzed using AutoDockVina. Results: A total of five compounds-related viruses were obtained from each SARS-CoV-2 protein with ideal and potential binding energy as a candidate for target protein inhibitor on SARS-CoV-2. At the protein 3CL protease imatinib, TAK-981, lopinavir, mefloquine, and sitagliptin were found to be potential inhibitors of this protein. In the protein RdRp tetrandrine, relacatib, AZD7986, imatinib, and TAK-981 revealed potential as an inhibitor of this protein. At the protein spike, glycoprotein AZD7986, selinexor, imatinib, lopinavir, and ciclesonide, were found to have potential as inhibitors of these proteins. All these compounds have better binding energy than the three comparator drugs (remdesivir, chloroquine, and hydroxychloroquine). Conclusion: We have obtained several compounds-related viruses with reliable binding energies to the SARS-CoV-2 proteins and potentially better than the three comparator drugs. Furthermore, this research will pave the way for accelerating the development of Covid-19 drugs.

scholarly journals The investigation of 2D monolayers as potential chelation agents in Alzheimer’s disease

2019 ◽  
Author(s):  
Neha Pavuluru ◽  
Xuan Luo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Charge Transfer ◽  
Binding Energy ◽  
Amyloid Beta ◽  
Density Functional ◽  
Density Functional Theory Calculations ◽  
Binding Energies ◽  
Amyloid Beta Protein ◽  
Functional Theory

In this study, we conducted Density Functional Theory calculations comparing the binding energy of the copper- Amyloid-beta complex to the binding energies of potential chelation materials. We used the first-coordination sphere of the truncated high-pH Amyloid-beta protein subject to computational limits. Binding energy and charge transfer calculations were evaluated for copper’s interaction with potential chelators: monolayer boron nitride, monolayer molybdenum disulfide, and monolayer silicene. Silicene produced the highest binding energies to copper, and the evidence of charge transfer between copper and the monolayer proves that there is a strong ionic bond present. Although our three monolayers did not directly present chelation potential, the absolute differences between the binding energies of the silicene binding sites and the Amyloid-beta binding site were minimal proving that further research in silicene chelators may be useful for therapy in Alzheimer’s disease.

scholarly journals Decoding Conformational Imprint of Convoluted Molecular Interactions Between Prenylflavonoids and Aggregated Amyloid-Beta42 Peptide Causing Alzheimer’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
E. Srinivasan ◽  
G. Chandrasekhar ◽  
P. Chandrasekar ◽  
K. Anbarasu ◽  
AS Vickram ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Senile Plaques ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Fibril Structure ◽  
Potential Inhibitors

Protein misfolding occurs due to the loss of native protein structure and adopts an abnormal structure, wherein the misfolded proteins accumulate and form aggregates, which result in the formation of amyloid fibrils that are associated with neurodegenerative diseases. Amyloid beta (Aβ42) aggregation or amyloidosis is contemplated as a unique hallmark characteristic of Alzheimer’s disease (AD). Due to aberrant accrual and aggregation of Aβ42 in extracellular space, the formation of senile plaques is found in AD patients. These senile plaques occur usually in the cognitive and memory region of the brain, enfeebles neurodegeneration, hinders the signaling between synapse, and disrupts neuronal functioning. In recent years, herbal compounds are identified and characterized for their potential as Aβ42 inhibitors. Thus, understanding their structure and molecular mechanics can provide an incredible finding in AD therapeutics. To describe the structure-based molecular studies in the rational designing of drugs against amyloid fibrils, we examined various herbal compounds that belong to prenylflavonoids. The present study characterizes the trends we identified at molecular docking studies and dynamics simulation where we observed stronger binding orientation of bavachalcone, bavachin, and neobavaisoflavone with the amyloid-beta (Aβ42) fibril structure. Hence, we could postulate that these herbal compounds could be potential inhibitors of Aβ42 fibrils; these anti-aggregation agents need to be considered in treating AD.

scholarly journals Emetine and Indirubin- 3- monoxime interaction with human brain acetylcholinesterase: A computational and statistical analysis

2022 ◽  
Vol 67 (4) ◽  
pp. 106-114
Author(s):  
Syed Sayeed Ahmad ◽  
Haroon Khan ◽  
Mohammad Khalid ◽  
Abdulraheem SA Almalki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Energy ◽  
Human Brain ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Docking Studies ◽  
Coefficient Of Determination ◽  
Intermolecular Energy ◽  
Brain Acetylcholinesterase

Alzheimer's disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date. It is characterized by a decrease in memory, associated with the mutilation of cholinergic neurotransmission. Presently, acetylcholinesterase inhibitors have emerged as the most endorsed pharmacological medications for the symptomatic treatment of mild to moderate Alzheimer's disease. This study aimed to research the molecular enzymatic inhibition of human brain acetylcholinesterase by a natural compound emetine and I3M. Molecular docking studies were used to identify superior interaction between enzyme acetylcholinesterase and ligands. Furthermore, the docked acetylcholinesterase-emetine complex was validated statistically using an analysis of variance in all tested conformers. In this interaction, H-bond, hydrophobic interaction, pi-pi, and Cation-pi interactions played a vital function in predicting the accurate conformation of the ligand that binds with the active site of acetylcholinesterase. The conformer with the lowest free energy of binding was further analyzed. The binding energy for acetylcholinesterase complex with emetine and I3M was -9.72kcal/mol and -7.09kcal/mol, respectively. In the current study, the prediction was studied to establish a relationship between binding energy and intermolecular energy (coefficient of determination [R2 linear = 0.999), and intermolecular energy and Van der wall forces (R2 linear = 0.994). These results would be useful in gaining structural insight for designing novel lead compounds against acetylcholinesterase for the effective management of Alzheimer's disease.

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.

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