Al-Aboudi Amal, Al-Qawasmeh Raed A, Shahwan Alaa, Mahmood Uzma, Khalid Asaad, Ul-Haq Zaheer
Department of Chemistry, The University of Jordan, Amman 11942, Jordan.
1] Department of Bioinformatics, Aligarh Institute of Technology, affiliated with Sir Syed University of Engineering & Technology, Gulshan-e-Iqbal, Block-5, Karachi 75300, Pakistan [2] Dr Panjwani Center for Molecular Medicine & Drug Research, International Center for Chemical & Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Acta Pharmacol Sin. 2015 Jul;36(7):879-86. doi: 10.1038/aps.2014.173. Epub 2015 May 4.
To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations.
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.
A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-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.
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.
利用分子对接模拟研究合成的金刚烷衍生物在胆碱酯酶内部的结合模式。
设计并合成了一系列含有金刚烷和酰肼部分的杂化化合物。在体外评估了它们对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的抑制活性。使用Sybyl7.3软件的Surflex-Dock程序包研究了这些化合物在胆碱酯酶内部的结合模式。
总共合成了26种金刚烷基衍生物。其中，金刚烷-1-羧酸酰肼对两种酶的抑制活性几乎相同，而其他10种化合物对BChE表现出中等抑制活性。分子对接研究表明，化合物与其活性位点周围残基之间的疏水相互作用起主要作用，同时也发现了亲水相互作用。当化合物对接至每种酶内部时，它们与BChE的相互作用比与AChE的相互作用更强，这可能是由于BChE的活性位点较大。估计的化合物对BChE和AChE的结合亲和力与实验数据一致。
新的金刚烷衍生物相对于AChE选择性抑制BChE，因此使其成为测试以下假设的良好候选物：在治疗阿尔茨海默病方面，BChE抑制剂比AChE抑制剂更有效且耐受性更好。
