In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes  

作　　者：Amal AL-ABOUDI Raed A AL-QAWASMEH Alaa SHAHWAN Uzma MAHMOOD Asaad KHALID Zaheer UbHAQ 

机构地区：[1]Department of Chemistry, The University of Jordan, Amman 11942, Jordan [2]Department of Bioinformatics, Aligarh Institute of Technology, affiliated with Sir Syed University of Engineering & Technology, Gulshan-e-lqbal, Block-5, Karachi 75300, Pakistan [3]Medicinal and Aromatic Plants Research Institute, National Center for Research, Khartoum-11111, Sudan [4]Dr Panjwani Center for Molecular Medicine & Drug Research, International Center for Chemical & Biological Sciences, University of Karachi, Karachi 75270, Pakistan

出　　处：《Acta Pharmacologica Sinica》2015年第7期879-886,共8页中国药理学报（英文版）

摘　　要：Aim： To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations. Methods： A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase （ACHE） and （butyrylcholinesterase） BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software. Results： A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-l-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over ACHE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data. Conclusion： The new adamantly derivatives selectively inhibit BChE with respect to ACHE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer＇s disease.Aim： To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations. Methods： A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase （ACHE） and （butyrylcholinesterase） BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software. Results： A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-l-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over ACHE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data. Conclusion： The new adamantly derivatives selectively inhibit BChE with respect to ACHE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer＇s disease.

关 键 词：N-arylidene-l-adamantylcarbohydrazides ADAMANTANE HYDRAZIDE cholinesterase inhibitor AIzheimer＇s disease ACETYLCHOLINESTERASE BUTYRYLCHOLINESTERASE molecular docking simulation 

分 类 号：TQ221[化学工程—有机化工] Q556[生物学—生物化学]