To find promising new multitargeted AD （Alzheimer＇s disease） inhibitors, the 3D-QSAR （three-dimensional quantitative structure-activity relationship） model for 32 AD inhibitors was established by using the CoMFA ...To find promising new multitargeted AD （Alzheimer＇s disease） inhibitors, the 3D-QSAR （three-dimensional quantitative structure-activity relationship） model for 32 AD inhibitors was established by using the CoMFA （comparative molecular field analysis） and CoMSIA （comparative molecular similarity index analysis） methods. Results showed that the CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient （q2） and a non-cross-validated coefficient （R2）, and the binding modes obtained by molecular docking were in agreement with the 3D-QSAR results, which suggests that the present 3D-QSAR model has good predictive capability to guide the design and structural modification of novel multitargeted AD inhibitors. Meanwhile, we found that one side of inhibitory molecule should be small group so that it would be conductive to enter the gorge to interact with the catalytic active sites of AChE （acetylcholinesterase）, and the other side of inhibitory molecule should be large group so that it would be favorable for interaction with the peripheral anionic site of ACHE. Furthermore, based on the 3D-QSAR model and the binding modes of AChE and [3-secretase （BACE-1）, the designed molecules could both act on dual binding sites of AChE （catalytic and peripheral sites） and dual targets （ACHE and BACE-1）. We hope that our results could provide hints for the design of new multitargeted AD derivatives with more potency and selective activity.展开更多
With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses a...With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients.展开更多
The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer＇s disease （A...The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer＇s disease （AD） treatment as an inhibitor of PS1/BACE1 interaction. 3-a-Akebonoic acid, which emanated from a high throughput screening （HTS）, was discovered to interfere with P S 1/BACE 1 interaction and reduce amyloid β-protein （Aβ） production. In view of the limited source, we instead used naturally rich betulinic acid （compound 2） as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship （SAR） of triterpenoid-type inhibitor of PS1/BACE1 interaction. Compound 22 was finally chosen as the most potent PS 1/BACE 1 interaction inhibitor, which reduced Aβgeneration effectively.展开更多
基金Acknowledgments The authors acknowledge the financial support of the Natural Science Foundation of Guangxi Province （No. 2013GXNSFAA019019） and the Natural Science Foundation of Guangxi Province （No. 2013GXNSFAA019041）.
文摘To find promising new multitargeted AD （Alzheimer＇s disease） inhibitors, the 3D-QSAR （three-dimensional quantitative structure-activity relationship） model for 32 AD inhibitors was established by using the CoMFA （comparative molecular field analysis） and CoMSIA （comparative molecular similarity index analysis） methods. Results showed that the CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient （q2） and a non-cross-validated coefficient （R2）, and the binding modes obtained by molecular docking were in agreement with the 3D-QSAR results, which suggests that the present 3D-QSAR model has good predictive capability to guide the design and structural modification of novel multitargeted AD inhibitors. Meanwhile, we found that one side of inhibitory molecule should be small group so that it would be conductive to enter the gorge to interact with the catalytic active sites of AChE （acetylcholinesterase）, and the other side of inhibitory molecule should be large group so that it would be favorable for interaction with the peripheral anionic site of ACHE. Furthermore, based on the 3D-QSAR model and the binding modes of AChE and [3-secretase （BACE-1）, the designed molecules could both act on dual binding sites of AChE （catalytic and peripheral sites） and dual targets （ACHE and BACE-1）. We hope that our results could provide hints for the design of new multitargeted AD derivatives with more potency and selective activity.
文摘With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients.
基金This research was supported by the National Natural Science Foundation of China （Nos. 81573267, 91413103 and 91213303）.
文摘The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer＇s disease （AD） treatment as an inhibitor of PS1/BACE1 interaction. 3-a-Akebonoic acid, which emanated from a high throughput screening （HTS）, was discovered to interfere with P S 1/BACE 1 interaction and reduce amyloid β-protein （Aβ） production. In view of the limited source, we instead used naturally rich betulinic acid （compound 2） as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship （SAR） of triterpenoid-type inhibitor of PS1/BACE1 interaction. Compound 22 was finally chosen as the most potent PS 1/BACE 1 interaction inhibitor, which reduced Aβgeneration effectively.
