Discovery of drug‐like acetylcholinesterase inhibitors by rapid virtual screening of a 6.9 million compound database

Miles, Jared A.; Ng, Jia Hui; Sreenivas, Bhaskara; Courageux, Charlotte; Igert, Alexandre; Dias, José; McGeary, Ross P.; Brazzolotto, Xavier; Ross, Benjamin P.

doi:10.1111/cbdd.13825

Cited by 5 publications

(6 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cynavimigenin A (5), cynaviminoside A (6), cynaviminoside B (7), and cynavimigenin B ( 8) were evaluated for their potential to elicit cholinergic toxicity by studying their inhibition of Electrophorus electricus acetylcholinesterase (Ee-AChE) and equine butyrylcholinesterase (eqBuChE), using previously described methods. 24,25 Although no significant activity was observed, 5−8 were relatively more potent inhibitors of eqBuChE than EeAChE when tested at 100 μM (compound, % inhibition of eqBuChE, % inhibition of EeAChE): 5 (7.72 ± 0.81%, 3.86 ± 0.42%); 6 (13.5 ± 1.19%, 4.39 ± 0.80%); 7 (2.64 ± 0.51%, 0.47 ± 1.73%); 8 (14.0 ± 1.12%, 4.30 ± 0.58%); and positive control cholinesterase inhibitor drug donepezil (91.3 ± 0.20%, 91.5 ± 0.93%).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

seco-Pregnane Glycosides from Australian Caustic Vine (Cynanchum viminale subsp. australe)

et al. 2023

Self Cite

View full text Add to dashboard Cite

Cynanchum viminale subsp. australe, more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for this species, along with use in traditional medicine and its potential anticancer activity. Disclosed herein are novel seco-pregnane aglycones cynavimigenin A (5) and cynaviminoside A ( 6), together with new pregnane glycosides cynaviminoside B (7) and cynavimigenin B (8). Cynavimigenin B (8) contains an unprecedented 7-oxobicyclo[2.2.1]heptane moiety in the seco-pregnane series, likely arising from a pinacol-type rearrangement. Interestingly, these isolates displayed only limited cytotoxicity in cancer and normal human cell lines, in addition to low activity against acetylcholinesterase and Sarcoptes scabiei bioassays, suggesting that 5−8 are not associated with the reported toxicity of this plant species.Cynanchum is a large genus of plants belonging to the Apocynaceae family (milkweed family, formerly Sarcostemma 1,2 ), consisting of over 200 species distributed worldwide. 3 Cynanchum species have long been used in Asia as traditional medicine for the treatment of common and chronic diseases. 3 Australia is home to around 13 native species of Cynanchum, occurring most commonly in northern Australia, 1,2,4 and certain species, in particular C. viminale subsp. australe (R.Br.) Mere & Liede, are known to have been used by Aboriginal peoples for the treatment of several conditions, including the topical treatment of wounds, cuts, and sores. 5 In addition, crude extracts of C. viminale subsp. australe have been reported to display cancer cell line cytotoxicity activity 6 and are especially active against skin cancer. 7 Interestingly, C. viminale subsp. australe has been reported to display toxicity toward livestock to varying extents all depending on location and/or drought, 8 which is also the case for a closely related Australian species, C. brevipedicellatum. 1 Livestock toxicity has also been observed in South Africa arising from other Cynanchum species and subspecies of C. viminale and was attributed to an abundance of pregnane glycosides 9,10 in the plant latex, such as sarcovimisides A−C (1−3) from C. viminale 11 and cynafoside A (4) from C. af ricanum 12 (Figure 1). Structurally, pregnane glycosides consist of a C 21 pregnane aglycone with a hydroxy group at C-3 and a substituent at C-17 and typically also contain an additional O-linked substituent at C-12. 9,10 The glycoside unit is typically comprised of a linear chain of mixed sugars, commonly glucose, rhamnose, and dideoxy sugars such as oleandrose, cymarose, or digitoxose. 9,10 While the most common aglycone motif within this family is 14β-hydroxypregnane, an increasing number of 14,15-and 8,14-seco-pregnane aglycones have been reported, along with a wider range of pharmacological effects. 13 Considering that very early attempts were unable to fully elucidate saponins from C. viminale subsp. australe, 14 and the Cynanchum genus aligns with our continued effort...

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

seco-Pregnane Glycosides from Australian Caustic Vine (Cynanchum viminale subsp. australe)

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is also noted that the hit compounds displayed acceptable ADME/T values during the QikProp analysis. The central nervous system activity prediction is one of the main properties during the ADME/T prediction [52]. All the compounds except DB12661 and DB07642 were exhibited at the in-active state, which is indicated by a CNS value of −2.…”

Section: Structural Properties Of Hit Compoundsmentioning

confidence: 99%

In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach

et al. 2021

View full text Add to dashboard Cite

The RAS–RAF–MEK–ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and is a gatekeeper for the many malignant effects of its downstream effector. Even though MEK inhibitors are under investigation in many cancers, drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Hence, we accomplished a high-throughput virtual screening to overcome this bottleneck by the discovery of dual-targeting therapy in cancer treatment. Here, a total of 11,808 DrugBank molecules were assessed through high-throughput virtual screening for their activity against MEK. Further, the Glide docking, MLSF and prime-MM/GBSA methods were implemented to extract the potential lead compounds from the database. Two compounds, DB012661 and DB07642, were outperformed in all the screening analyses. Further, the study results reveal that the lead compounds also have a significant binding capability with the co-target PIM1. Finally, the SIE-based free energy calculation reveals that the binding of compounds was majorly affected by the van der Waals interactions with MEK receptor. Overall, the in silico binding efficacy of these lead compounds against both MEK and PIM1 could be of significant therapeutic interest to overcome drug resistance in the near future.

show abstract

“…Currently, the main therapy for AD ranging from mild to severe AD are the cholinesterase inhibitors (ChEIs) [ 30 , 31 ]. Positive cognitive and global symptomatic effects of ChEI therapy have been reported in a randomized clinical trial [ 32 ] and observational studies [ 33 , 34 , 35 ] for both EOAD and LOAD [ 5 ]. While LOAD has been reported to present more functional deficits and severities than the EOAD [ 36 ], possible differences in demographic and other pharmacological factors in patients treated with and without ChEIs, and how this might contribute to a gender difference in a cohort with exclusively LOAD is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Gender Differences in Demographic and Pharmacological Factors in Patients Diagnosed with Late-Onset of Alzheimer’s Disease

et al. 2022

View full text Add to dashboard Cite

Background: Whether gender differences exist in late-onset of Alzheimer’s disease (LOAD) treated with cholinesterase inhibitors (ChEIs) is not fully understood. This study investigated demographic and pharmacological characteristics in LOAD patients to determine gender differences in LOAD patients treated with ChEIs alone and ChEIs with other medications. Methods: This 5-year retrospective data analysis included 9290 LOAD AD patients with 2949 men patients and 6341 women. Potential predictors of demographic and pharmacological characteristics associated gender differences in patients treated with and without ChEIs therapy were determined using univariate analysis, while multivariable models adjusted for demographic and pharmacological variables. Results: In the adjusted analysis, men patients with LOAD that presented with a history of alcohol use (ETOH) (OR = 1.339, 95% CI, 1.072–1.672, p = 0.010), treated with second generation antipsychotics (SGAs) (OR = 1.271, 95% CI, 1.003–1.610, p = 0.047), citalopram (OR = 5.103, 95% CI, 3.423–7.607, p < 0.001), memantine (OR = 4.409, 95% CI, 3.704–5.249, p < 0.001), and buspirone (OR = 2.166, 95% CI, 1.437–3.264, p < 0.001) were more likely to receive ChEIs therapy, whereas older men were less likely to be treated with ChEIs therapy. Women who were African Americans (OR = 1.387, 95% CI, 1.168–1.647, p < 0.001), that received memantine (OR = 3.412, 95% CI, 3.034–3.837, p < 0.001), selective serotonin reuptake inhibitor (SSRIs) (OR = 1.143, 95% CI, 1.016–1.287, p = 0.026), and a history of ETOH (OR = 2.109, 95% CI, 1.724–2.580, p < 0.001) were more likely to receive ChEIs therapy, whereas older women were less likely to receive ChEIs therapy. Conclusion: In both men and women patients, those with increasing age were less likely to be treated with ChEI therapy, while patients treated with memantine were also likely to receive ChEI therapy. Our findings highlight the importance for clinicians to optimize ChEI in LOAD to improve treatment effectiveness and eliminate gender differences in ChEI therapy.

show abstract

Discovery of drug‐like acetylcholinesterase inhibitors by rapid virtual screening of a 6.9 million compound database

Cited by 5 publications

References 36 publications

seco-Pregnane Glycosides from Australian Caustic Vine (Cynanchum viminale subsp. australe)

seco-Pregnane Glycosides from Australian Caustic Vine (Cynanchum viminale subsp. australe)

In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach

Gender Differences in Demographic and Pharmacological Factors in Patients Diagnosed with Late-Onset of Alzheimer’s Disease

Contact Info

Product

Resources

About