scholarly journals Virtual Screening and Biological Evaluation of Piperazine Derivatives as Human Acetylcholinesterase Inhibitors

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Kavitha Raj Varadaraju ◽  
Jajur Ramanna Kumar ◽  
Lingappa Mallesha ◽  
Archana Muruli ◽  
Kikkeri Narasimha Shetty Mohana ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Hydrophobic Interactions ◽  
Acetylcholinesterase Inhibitors ◽  
Biological Evaluation ◽  
Anionic Site ◽  
Amyloid Peptides ◽  
Lipinski’S Rule ◽  
Piperazine Derivatives ◽  
Catalytic Sites ◽  
Lipinski’S Rule Of Five

The piperazine derivatives have been shown to inhibit human acetylcholinesterase. Virtual screening by molecular docking of piperazine derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K), 4-(4-methyl)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S1), and 4-(4-chloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S3) has been shown to bind at peripheral anionic site and catalytic sites, whereas 4-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S4) and 4-(2,5-dichloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S7) do not bind either to peripheral anionic site or catalytic site with hydrogen bond. All the derivatives have differed in number of H-bonds and hydrophobic interactions. The peripheral anionic site interacting molecules have proven to be potential therapeutics in inhibiting amyloid peptides aggregation in Alzheimer’s disease. All the piperazine derivatives follow Lipinski’s rule of five. Among all the derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K) was found to have the lowest TPSA value.

scholarly journals Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski’s Rule of Five and ZINC Databank

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Pablo Andrei Nogara ◽  
Rogério de Aquino Saraiva ◽  
Diones Caeran Bueno ◽  
Lílian Juliana Lissner ◽  
Cristiane Lenz Dalla Corte ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Ache Activity ◽  
Acetylcholinesterase Inhibitors ◽  
Behavioral Changes ◽  
Lipinski’S Rule ◽  
Memory Impairments ◽  
Compound C ◽  
Lipinski’S Rule Of Five

Alzheimer’s disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski’s rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and furtherin vitroassays were performed to analyze the most potent inhibitors through the IC50value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) fromEquus ferus(EfBChE), with IC50ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor ofEfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.

Discovery of new multifunctional selective acetylcholinesterase inhibitors: structure-based virtual screening and biological evaluation

2019 ◽  
Vol 33 (5) ◽  
pp. 521-530 ◽  
Author(s):  
Cheng-Shi Jiang ◽  
Yong-Xi Ge ◽  
Zhi-Qiang Cheng ◽  
Jia-Li Song ◽  
Yin-Yin Wang ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Acetylcholinesterase Inhibitors ◽  
Biological Evaluation

scholarly journals Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4895
Author(s):  
Paptawan Suwanhom ◽  
Jirakrit Saetang ◽  
Pasarat Khongkow ◽  
Teerapat Nualnoi ◽  
Varomyalin Tipmanee ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
In Silico ◽  
Acetylcholinesterase Inhibitors ◽  
Biological Evaluation ◽  
Anionic Site ◽  
Human Neuroblastoma ◽  
Ache Inhibitors ◽  
In Silico Studies ◽  
Quinoxaline Derivatives ◽  
Ic50 Values

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.

scholarly journals Structure-Based Virtual Screening and Biological Evaluation of Peptide Inhibitors for Polo-Box Domain

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 107 ◽  
Author(s):  
Fang Yan ◽  
Guangmei Liu ◽  
Tingting Chen ◽  
Xiaochen Fu ◽  
Miao-Miao Niu
Keyword(s):  
Cell Cycle ◽  
Virtual Screening ◽  
Fold Increase ◽  
Pharmacophore Modeling ◽  
Biological Evaluation ◽  
Peptide Inhibitors ◽  
Regulatory Proteins ◽  
Competitive Binding Assay ◽  
M Phase ◽  
Cell Cycle Regulatory Proteins

The polo-box domain of polo-like kinase 1 (PLK1-PBD) is proved to have crucial roles in cell proliferation. Designing PLK1-PBD inhibitors is challenging due to their poor cellular penetration. In this study, we applied a virtual screening workflow based on a combination of structure-based pharmacophore modeling with molecular docking screening techniques, so as to discover potent PLK1-PBD peptide inhibitors. The resulting 9 virtual screening peptides showed affinities for PLK1-PBD in a competitive binding assay. In particular, peptide 5 exhibited an approximately 100-fold increase in inhibitory activity (IC50 = 70 nM), as compared with the control poloboxtide. Moreover, cell cycle experiments indicated that peptide 5 effectively inhibited the expression of p-Cdc25C and cell cycle regulatory proteins by affecting the function of PLK1-PBD, thereby inducing mitotic arrest at the G2/M phase. Overall, peptide 5 can serve as a potent lead for further investigation as PLK1-PBD inhibitors.

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