Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues

Gogoi, Dhrubajyoti; Chaliha, Amrita Kashyap; Sarma, Diganta; Kakoti, Bibhuti Bhusan; Buragohain, Alak Kumar

doi:10.1016/j.biopha.2016.11.076

Cited by 9 publications

(4 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to frontier molecular orbital theory, the HOMO energy is related to the ionization potential, whereas the LUMO energy is associated with electron affinity. The HOMO has the tendency to donate electrons in the first place, while the LUMO has the priority to accept electrons, and both are indicators of the possible electrophilic and nucleophilic attack sites in the molecule, respectively. , A low energy gap is usually predictive of a reactive compound, while a wide energy gap implies that the activity of the compound is not sufficient at the active site of a protein receptor . The distribution of HOMO and LUMO of the three hits and DMBF is depicted in Figure .…”

Section: Results and Discussionmentioning

confidence: 99%

Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations

Gao

Zhang

et al. 2020

J. Agric. Food Chem.

View full text Add to dashboard Cite

Broflanilide, a novel insecticide, is classified as a negative allosteric modulator (NAM) of insect γ-aminobutyric acid (GABA) receptors (GABARs) as desmethyl-broflanilide (DMBF) allosterically inhibits the GABA-induced responses. The G277M mutation of the Drosophila melanogaster GABAR subunit has been reported to abolish the inhibitory activity of DMBF. The binding mode of DMBF in insect GABARs needs to be clarified to understand the underlying mechanism of this mutation and to develop novel, efficient NAMs of insect GABARs. Here, we found that a hydrogen bond formed between DMBF and G277 of the D. melanogaster GABAR model might be the key interaction for the antagonism of DMBF by in silico simulations. The volume increase induced by the G277M mutation blocks the entrance of the binding pocket, making it difficult for DMBF to enter the binding pocket and thereby decreasing its activity. The following virtual screening and bioassay results identified a novel NAM candidate of insect GABARs. Overall, we reported a possible binding mode of DMBF in insect GABARs and proposed the insensitivity mechanism of the G277M mutant GABAR to DMBF using molecular simulations. The identified NAM candidates might provide more alternatives or potentials for the design of GABAR-targeting insecticides.

show abstract

Section: Results and Discussionmentioning

confidence: 99%

Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations

Gao

Zhang

et al. 2020

J. Agric. Food Chem.

View full text Add to dashboard Cite

show abstract

“…However, the pharmacophore model is derived from active compounds with different frameworks and generates the relevant pharmacophore characteristics to show the common features of active small molecules. That is, if a small molecule possesses the characteristics of a pharmacophore, then it may have a certain biological activity (Patel et al, 2002;Vlachakis et al, 2015;Gogoi et al, 2017). In our previous studies, we identified several structurally diverse active compounds out of in 130 amino alcohols, which is suitable for generating a pharmacophore model.…”

Section: Discussionmentioning

confidence: 99%

“…Normally, the pharmacophore model can be generated by receptor-based and ligand-based methods. The former method relies on knowing the structure of the target (protein, DNA and so on) to analyse the interactions in the ligand-receptor complex (Gao et al, 2017;Kumar, 2018), while the latter method is based on the structures of the active compounds (Patel et al, 2002;Gogoi et al, 2017). Because the target of the series of amino alcohols involved in this study is unknown, a ligand-based approach was used to generate the pharmacophore model.…”

Section: Discussionmentioning

confidence: 99%

Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds

Liu

Yin

Yao

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Echinococcosis is a serious helminthic zoonosis with a great impact on human health and livestock husbandry. However, the clinically used drugs (benzimidazoles) have a low cure rate, so alternative drugs are urgently needed. Currently, drug screenings for echinococcosis are mainly phenotype-based, and the efficiency of identifying active compounds is very low. With a pharmacophore model generated from the structures of active amino alcohols, we performed a virtual screening to discover novel compounds with anti-echinococcal activity. Sixty-two compounds from the virtual screening were tested on Echinococcus multilocularis protoscoleces, and 10 of these compounds were found to be active. After further evaluation of their cytotoxicity, S6 was selected along with two active amino alcohols for in vivo pharmacodynamic and pharmacokinetic studies. At the two tested doses (50 and 25 mg/kg), S6 inhibited the growth of E. multilocularis in mice (14.43 and 9.53%), but no significant difference between the treatment groups and control group was observed. Treatment with BTB4 and HT3 was shown to be ineffective. During the 28 days of treatment, the death of mice in the mebendazole, HT3, and BTB4 groups indicated their toxicity. The plasma concentration of S6 administered by both methods was very low, with the C max being only 1 ng/ml after oral administration and below the detection limit after intramuscular administration. In addition, the plasma concentrations of BTB4 and HT3 in vitro did not reach high enough levels to kill the parasites. The toxicities of these two amino alcohols indicated that they are not suitable for further development as anti-echinococcal drugs. However, further attempts should be made to increase the bioavailability of S6 and modify its structure. In this study, we demonstrate that pharmacophore-based virtual screenings with high drug identification efficiency could be used to find novel drugs for treating echinococcosis.

show abstract

“…In this aspect, we focused on 15 VS studies, published between 2015 and 2020, that verified the inhibitory activity of potential ChEIs in bioassays. There are many other examples of studies utilizing LBVS and SBVS to search for ChEIs; − however, they did not confirm the activity of the in silico hits using in vitro experimental techniques or discovered very weak inhibitors; hence, these studies were omitted from this Review.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Virtual Screening for Cholinesterase Inhibitors

Miles

Ross

2020

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a significant health crisis, and current treatments provide only limited benefits to cognition at the cost of serious side effects. Recently, virtual screening techniques such as ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) have emerged as powerful drug discovery tools for identifying potential ligands of a biological target from a large database of chemical structures. The cholinesterases are an AD target particularly well suited for drug discovery using virtual screening due to their well-characterized active sites and comprehensive understanding of the structure–activity relationships of existing inhibitors. Over the last 5 years (2015–2020), at least 15 studies have used virtual screening techniques to discover potent new cholinesterase inhibitors. Herein we review how LBVS and SBVS have been applied individually or in tandem to discover novel acetylcholinesterase and butyrylcholinesterase inhibitors for AD, and highlight the need to confirm in vitro activity of screening compounds.

show abstract

Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues

Cited by 9 publications

References 45 publications

Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations

Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations

Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds

Recent Advances in Virtual Screening for Cholinesterase Inhibitors

Contact Info

Product

Resources

About