Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

Abstract

In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer's randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties.

Rational design, cognition and neuropathology evaluation of QTC-4-MeOBnE in a streptozotocin-induced mouse model of sporadic Alzheimer’s disease

“…The cholinergic synapses are selectively vulnerable to Aβ oligomer toxicity, being drastically affected by neurodegeneration 13 . In addition, structural studies have pointed to the dual inhibition of AChE (catalytic active site (CAS) and peripheral anionic site (PAS) that can reduce both the cholinergic deficit and Aβ deposition 14 .…”

Virtual Screening and Statistical Analysis in the Design of New Caffeine Analogues Molecules with Potential Epithelial Anticancer Activity

“…The tetra-parametric model can be considered the most reliable of the models, regarding the prediction of pICT 50 values, also due to statistical consistencies observed from the regression data (R, R 2 , R A 2 , SEE e teste t) discussed above. The statistically significant values presented provide confidence to the MLR models and their predictive capacity [ 29 , 30 ].…”

In Vitro Evaluation and Docking Studies of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde Derivatives as Potential Anti-Alzheimer’s Agents

“…AChE has been found to predominate over BChE in the healthy brains, however, its activity is known to decline during the development of AD while BChE activity increases. Although selective inhibition of BChE can lead to adverse peripheral side effects [33], compound 3d , which is selective against BChE activity, may be more beneficial in alleviating the cognitive symptoms on moderate forms of AD. The presence of the hydrazono moiety in the case of the 4-methoxyphenyl substituted derivative 3f (IC 50 values of 5.4 µM and 9.6 µM, respectively) led to a reverse trend in inhibitory effect to that of 2f (IC 50 = 9.4 and 5.1 μM, respectively) against AChE and BChE activities.…”