scholarly journals Development of Dual Inhibitors against Alzheimer’s Disease Using Fragment-Based QSAR and Molecular Docking

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Manisha Goyal ◽  
Jaspreet Kaur Dhanjal ◽  
Sukriti Goyal ◽  
Chetna Tyagi ◽  
Rabia Hamid ◽  
...  
Keyword(s):  
Biological Activity ◽  
Molecular Docking ◽  
Drug Targets ◽  
Combinatorial Library ◽  
Interaction Analysis ◽  
Site Specific ◽  
Cleavage Enzyme ◽  
Dual Inhibitors ◽  
Dual Inhibition ◽  
Bace 1

Alzheimer’s (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression.β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BACE-1 and AChE. The GQSAR model provides site-specific clues about the molecules where certain modifications can result in increased biological activity. This information could be of high value for design and development of multifunctional drugs for combating AD.

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.

Quantitative structure-activity relationship model, molecular docking simulation and computational design of some novel compounds against DNA gyrase receptor.

2020 ◽  
Vol 16 ◽  
Author(s):  
Shola Elijah Adeniji
Keyword(s):  
Biological Activity ◽  
Molecular Docking ◽  
Binding Energy ◽  
Biological Activities ◽  
Docking Simulation ◽  
Dna Gyrase ◽  
Computational Design ◽  
Multi Drug Resistance ◽  
Drug Candidate ◽  
Standard Drug

Introduction: Mycobacterium tuberculosis has instigated a serious challenge toward the effective treatment of tuberculosis. The reoccurrence of the resistant strains of the disease to accessible drugs/medications has mandate for the development of more effective anti-tubercular agents with efficient activities. Time expended and costs in discovering and synthesizing new hypothetical drugs with improved biological activity have been a major challenge toward the treatment of multi-drug resistance strain M. tuberculosis (TB). Meanwhile, to solve the problem stated, a new approach i.e. QSAR which establish connection between novel drugs with a better biological against M. tuberculosis is adopted. Methods: The anti-tubercular model established in this study to forecast the biological activities of some anti-tubercular compounds selected and to design new hypothetical drugs is subjective to the molecular descriptors; MATS7s, SM1_DzZ, SpMin4_Bhv, TDB3v and RDF70v. Ligand-receptor interactions between quinoline derivatives and the receptor (DNA gyrase) was carried out using molecular docking technique by employing the PyRx virtual screening software and discovery studio visualizer software. Furthermore, docking study indicates that compounds 20 of the derivatives with promising biological activity have the utmost binding energy of -17.79 kcal/mol. Results: Meanwhile, the interaction of the standard drug; isoniazid with the target enzyme was observed with the binding energy -14.6 kcal/mol which was significantly lesser than the binding energy of the ligand (compound 20).Therefore, compound 20 served as a template structure to designed compounds with more efficient activities. Among the compounds designed; compounds 20p was observed with better anti-tubercular activities with more prominent binding affinities of -24.3kcal/mol. Conclusion: The presumption of this research aid the medicinal chemists and pharmacist to design and synthesis a novel drug candidate against the tuberculosis. Moreover, in-vitro and in-vivo test could be carried out to validate the computational results.

scholarly journals New Mononuclear and Binuclear Cu(II), Co(II), Ni(II), and Zn(II) Thiosemicarbazone Complexes with Potential Biological Activity: Antimicrobial and Molecular Docking Study

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2288
Author(s):  
Ahmed Gaber ◽  
Moamen S. Refat ◽  
Arafa A.M. Belal ◽  
Ibrahim M. El-Deen ◽  
Nader Hassan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Biological Activity ◽  
Molecular Docking ◽  
Metal Complexes ◽  
Analytical Data ◽  
Docking Study ◽  
Spectroscopic Techniques ◽  
Molecular Docking Study ◽  
Tetrahedral Geometry ◽  
Thiosemicarbazone Complexes

Herein, we report the synthesis of eight new mononuclear and binuclear Co2+, Ni2+, Cu2+, and Zn2+ methoxy thiosemicarbazone (MTSC) complexes aiming at obtaining thiosemicarbazone complex with potent biological activity. The structure of the MTSC ligand and its metal complexes was fully characterized by elemental analysis, spectroscopic techniques (NMR, FTIR, UV-Vis), molar conductivity, thermogravimetric analysis (TG), and thermal differential analysis (DrTGA). The spectral and analytical data revealed that the obtained thiosemicarbazone-metal complexes have octahedral geometry around the metal center, except for the Zn2+-thiosemicarbazone complexes, which showed a tetrahedral geometry. The antibacterial and antifungal activities of the MTSC ligand and its (Co2+, Ni2+, Cu2+, and Zn2+) metal complexes were also investigated. Interestingly, the antibacterial activity of MTSC- metal complexes against examined bacteria was higher than that of the MTSC alone, which indicates that metal complexation improved the antibacterial activity of the parent ligand. Among different metal complexes, the MTSC- mono- and binuclear Cu2+ complexes showed significant antibacterial activity against Bacillus subtilis and Proteus vulgaris, better than that of the standard gentamycin drug. The in silico molecular docking study has revealed that the MTSC ligand could be a potential inhibitor for the oxidoreductase protein.

scholarly journals In Silico Molecular Docking and Interaction Analysis of Traditional Chinese Medicines Against SARS-CoV-2 Receptor

2021 ◽  
Vol 16 (5) ◽  
pp. 1934578X2110150
Author(s):  
Gang Li ◽  
Wei Zhou ◽  
Xiurong Zhao ◽  
Ying Xie
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Interaction Analysis ◽  
Herbal Remedies ◽  
Receptor Protein ◽  
Stable Complex ◽  
Traditional Chinese Medicines ◽  
Ligand Interaction ◽  
Chinese Medicines ◽  
In Silico Molecular Docking

The novel coronavirus, 2019-nCoV, has led to a major pandemic in 2020 and is responsible for more than 2.9 million officially recorded deaths worldwide. As well as synthetic anti-viral drugs, there is also a need to explore natural herbal remedies. The Traditional Chinese Medicines (TCMs) system has been used for thousands of years for the prevention, diagnosis, and treatment of several chronic diseases. In this paper, we performed an in silico molecular docking and interaction analysis of TCMs against SARS-CoV-2 receptor RNA-dependent RNA polymerase (RdRp). We obtained the 5 most effective plant compounds which had a better binding affinity towards the target receptor protein. These compounds areforsythoside A, rutin, ginkgolide C, icariside II, and nolinospiroside E. The top-ranked compound, based on docking score, was nolinospiroside, a glycoside found in Ophiopogon japonicas that has antioxidant properties. Protein-ligand interaction analysis discerned that nolinospiroside formed a strong bond between ARG 349 of the protein receptor and the carboxylate group of the ligand, forming a stable complex. Hence, nolinospiroside could be deployed as a lead compound against SARS-CoV-2 infection that can be further investigated for its potential benefits in curbing the viral infection.

scholarly journals Hydrazones of 4-(Trifluoromethyl)benzohydrazide as New Inhibitors of Acetyl- and Butyrylcholinesterase

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 989
Author(s):  
Martin Krátký ◽  
Katarína Svrčková ◽  
Quynh Anh Vu ◽  
Šárka Štěpánková ◽  
Jarmila Vinšová
Keyword(s):  
Biological Activity ◽  
Mixed Type ◽  
Cholinesterase Inhibitors ◽  
Eukaryotic Cell ◽  
Structure Activity ◽  
Aliphatic Ketones ◽  
Ic50 Values ◽  
Central Nervous Systems ◽  
Dual Inhibition ◽  
Potential Inhibitors

Based on the broad spectrum of biological activity of hydrazide–hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using Ellman’s spectrophotometric method. The hydrazide–hydrazones produced a dual inhibition of both cholinesterase enzymes with IC50 values of 46.8–137.7 µM and 19.1–881.1 µM for AChE and BuChE, respectively. The majority of the compounds were stronger inhibitors of AChE; four of them (2-bromobenzaldehyde, 3-(trifluoromethyl)benzaldehyde, cyclohexanone, and camphor-based 2o, 2p, 3c, and 3d, respectively) produced a balanced inhibition of the enzymes and only 2-chloro/trifluoromethyl benzylidene derivatives 2d and 2q were found to be more potent inhibitors of BuChE. 4-(Trifluoromethyl)-N’-[4-(trifluoromethyl)benzylidene]benzohydrazide 2l produced the strongest inhibition of AChE via mixed-type inhibition determined experimentally. Structure–activity relationships were identified. The compounds fit physicochemical space for targeting central nervous systems with no apparent cytotoxicity for eukaryotic cell line together. The study provides new insights into this CF3-hydrazide–hydrazone scaffold.

Structural, QSAR, machine learning and molecular docking studies of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 receptor antagonists

2021 ◽  
Author(s):  
Riad Hanachi ◽  
Ridha Ben Said ◽  
Hamza Allal ◽  
Seyfeddine Rahali ◽  
Mohammed A. M. Alkhalifah ◽  
...  
Keyword(s):  
Machine Learning ◽  
Biological Activity ◽  
Molecular Docking ◽  
Theoretical Analysis ◽  
Structural Study ◽  
Docking Studies ◽  
Pyrazole Derivatives ◽  
Molecular Docking Studies ◽  
Cannabinoid 1 Receptor ◽  
Chemical Descriptors

We performed a structural study followed by a theoretical analysis of the chemical descriptors and the biological activity of a series of 5-thiophen-2-yl pyrazole derivatives as potent and selective Cannabinoid-1...

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