scholarly journals Molecular Modeling Studies of Piperidine Derivatives as New Acetylcholinesterase Inhibitors against Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Elaine F. F. da Cunha ◽  
José E. Resende ◽  
Tanos C. C. Franca ◽  
Mateus Aquino Gonçalves ◽  
Felipe R. de Souza ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modeling ◽  
Neurodegenerative Disorders ◽  
Acetylcholinesterase Inhibitors ◽  
Molecular Target ◽  
New Drugs ◽  
Ache Inhibitors ◽  
Progressive Loss ◽  
Molecular Modeling Studies ◽  
Dynamics Simulations

Neurodegenerative disorders are related to the progressive loss of structure or function and, eventually, death of neurons. These processes are responsible for diseases like Parkinson’s, Alzheimer’s, and Huntington’s, and the main molecular target for the drug design against these illnesses today is the enzyme acetylcholinesterase (AChE). Following this line, in the present work, we applied docking techniques to study some piperidine derivative inhibitors of AChE and further propose structures of six new AChE inhibitors as potential new drugs against neurodegenerative disorders. The best inhibitor proposed was submitted to additional molecular dynamics simulations steps.

Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamics Simulations Techniques

2020 ◽  
Vol 16 (7) ◽  
pp. 903-927 ◽  
Author(s):  
Rahman Abdizadeh ◽  
Farzin Hadizadeh ◽  
Tooba Abdizadeh
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
Molecular Dynamics Simulations ◽  
Data Set ◽  
Ache Inhibitors ◽  
Modeling Studies ◽  
Qsar Models ◽  
Molecular Modeling Studies ◽  
Dynamics Simulations

Background: Acetylcholinesterase (AChE), a serine hydrolase, is an important drug target in the treatment of Alzheimer's disease (AD). Thus, novel AChE inhibitors were designed and developed as potential drug candidates, for significant therapy of AD. Objective: In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA, HQSAR and molecular docking and molecular dynamics simulations were performed on a series of AChE inhibitors to get more potent anti-Alzheimer drugs. Methods: 2D/3D-QSAR models including CoMFA, CoMFA-RF, CoMSIA, and HQSAR methods were carried out on 40 pyrimidinylthiourea derivatives as data set by the Sybylx1.2 program. Molecular docking and molecular dynamics simulations were performed using the MOE software and the Sybyl program, respectively. Partial least squares (PLS) model as descriptors was used for QSAR model generation. Results: The CoMFA (q2, 0.629; r2ncv, 0.901; r2pred, 0.773), CoMFA-RF (q2, 0.775; r2ncv, 0.910; r2pred, 0.824), CoMSIA (q2, 0.754; r2ncv, 0.919; r2pred, 0.874) and HQSAR models (q2, 0.823; r2ncv, 0.976; r2pred, 0.854) for training and test set yielded significant statistical results. Conclusion: These QSAR models were excellent, robust and had good predictive capability. Contour maps obtained from the QSAR models were validated by molecular dynamics simulationassisted molecular docking study. The resulted QSAR models could be useful for the rational design of novel potent AChE inhibitors in Alzheimer's treatment.

Molecular modeling studies to characterize N-phenylpyrimidin-2-amine selectivity for CDK2 and CDK4 through 3D-QSAR and molecular dynamics simulations

2016 ◽  
Vol 12 (4) ◽  
pp. 1250-1268 ◽  
Author(s):  
Tahir Ali Chohan ◽  
Jiong-Jiong Chen ◽  
Hai-Yan Qian ◽  
You-Lu Pan ◽  
Jian-Zhong Chen
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modeling ◽  
Molecular Dynamics Simulations ◽  
3D Qsar ◽  
Structure Activity ◽  
Modeling Studies ◽  
Molecular Modeling Studies ◽  
Dynamics Simulations

Molecular modeling simulations were carried out to understand the structure–activity and selectivity correlation of N-phenylpyrimidin-2-amines binding to CDK2 and CDK4.

Design of Inhibitors for Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Enzyme of Leishmania mexicana

2020 ◽  
Vol 16 (6) ◽  
pp. 784-795
Author(s):  
Krisnna M.A. Alves ◽  
Fábio José Bonfim Cardoso ◽  
Kathia M. Honorio ◽  
Fábio A. de Molfetta
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Point Of View ◽  
New Drugs ◽  
Leishmania Mexicana ◽  
Receptor Complexes ◽  
Starting Point ◽  
Dynamics Simulations ◽  
Selection Of

Background:: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3- phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease. Objective:: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in Leishmania mexicana (L. mexicana). Methods: A search for novel antileishmanial molecules was carried out based on similarities from the pharmacophoric point of view related to the binding site of the crystallographic enzyme using the ZINCPharmer server. The molecules selected in this screening were subjected to molecular docking and molecular dynamics simulations. Results:: Consensual analysis of the docking energy values was performed, resulting in the selection of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze the main interactions and subjected to toxicophoric evaluation, culminating in the selection of three compounds, which were subsequently submitted to molecular dynamics simulations. The docking results showed that the selected compounds interacted with GAPDH from L. mexicana, especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results obtained from molecular dynamics, it was observed that one of the loop regions, corresponding to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting in the positioning and the molecular recognition via residues responsible for the catalytic activity. Conclusion:: he use of molecular modeling techniques enabled the identification of promising compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here can serve as a starting point to design new and more effective compounds than those currently available.

scholarly journals Evaluation of the effects of acetylcholinesterase inhibitors in the zebrafish touch-evoked response: quantitative vs. qualitative assessment

2020 ◽  
Vol 32 (1) ◽  
Author(s):  
Laura Guzman ◽  
Gisela Besa ◽  
Daniela Linares ◽  
Lara González ◽  
Caterina Pont ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Acetylcholinesterase Inhibitors ◽  
Cost Effective ◽  
Evoked Response ◽  
New Drugs ◽  
Screening Tools ◽  
Qualitative Assessment ◽  
Toxicity Screening ◽  
Novel Treatments ◽  
Ache Inhibitors

Abstract Background The difficulty of finding new treatments for neurological diseases with great impact in our society like Alzheimer’s disease can be ascribed in part to the complexity of the nervous system and the lack of quick and cost-effective screening tools. Such tools could not only help to identify potential novel treatments, but could also be used to test environmental contaminants for their potential to cause neurotoxicity. It has been estimated that 5–10% of the anthropogenic chemicals are developmental neurotoxic (DNT) and exposure to DNT compounds has been linked to several neurological diseases. Within this study we were testing the applicability of a quick and cost-effective behavioural test using zebrafish embryos: the touch-evoked response assay, in this case, an assay evaluating the swimming response to a tap in the tail. Two acetylcholinesterase (AChE) inhibitors positive controls (paraoxon and huprine Y), as well as 10 huprine-derivative compounds were tested and the results were evaluated using 2 different methods, a quantitative and a qualitative one. Results We could show that the methodology presented is able to detect behavioural effects of AChE inhibitors. A good correlation between the results obtained with the quantitative and the qualitative method was obtained (R2 = 0.84). Conclusions Our proposed method enables combination of screening for new drugs with toxicity screening in a whole embryo model alternative to animal experimentation, thereby merging 2 drug development steps into one.

Deciphering the GPER/GPR30-agonist and antagonists interactions using molecular modeling studies, molecular dynamics, and docking simulations

2015 ◽  
Vol 33 (10) ◽  
pp. 2161-2172 ◽  
Author(s):  
D. Méndez-Luna ◽  
M. Martínez-Archundia ◽  
Rachid C. Maroun ◽  
G. Ceballos-Reyes ◽  
M.J. Fragoso-Vázquez ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modeling ◽  
Docking Simulations ◽  
Modeling Studies ◽  
Molecular Modeling Studies
Sign in / Sign up

Export Citation Format

Share Document