Discovery and Biological Evaluation of New Selective Acetylcholinesterase Inhibitors with Anti-Aβ Aggregation Activity through Molecular Docking-Based Virtual Screening

In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Aβ1–42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Aβ1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.

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Pharmacophore based virtual screening, molecular docking and biological evaluation to identify novel PDE5 inhibitors with vasodilatory activity

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2014.05.004 ◽

2014 ◽

Vol 24 (14) ◽

pp. 3137-3141 ◽

Cited By ~ 26

Author(s):

Anupama Mittal ◽

Sarvesh Paliwal ◽

Mukta Sharma ◽

Aarti Singh ◽

Swapnil Sharma ◽

...

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Biological Evaluation ◽

Pde5 Inhibitors ◽

Vasodilatory Activity

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Discovery of HIV-1 Integrase Inhibitors: Pharmacophore Mapping, Virtual Screening, Molecular Docking, Synthesis, and Biological Evaluation

Chemical Biology & Drug Design ◽

10.1111/cbdd.12207 ◽

2013 ◽

Vol 83 (2) ◽

pp. 154-166 ◽

Cited By ~ 7

Author(s):

Hardik Bhatt ◽

Paresh Patel ◽

Christophe Pannecouque

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Biological Evaluation ◽

Integrase Inhibitors ◽

Pharmacophore Mapping ◽

Synthesis And Biological Evaluation ◽

Hiv 1

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Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors

Molecules ◽

10.3390/molecules24234258 ◽

2019 ◽

Vol 24 (23) ◽

pp. 4258 ◽

Cited By ~ 1

Author(s):

Yunjiang Zhou ◽

Shi Tang ◽

Tingting Chen ◽

Miao-Miao Niu

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

A549 Cells ◽

Pharmacophore Modeling ◽

Biological Evaluation ◽

Human Lung Cancer ◽

Dependent Manner ◽

Biological Processes ◽

Dose Dependent ◽

Parp 1

Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 μM). MTT assay confirmed that compounds 1–4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer.

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