caa a22 4500 605512353 CHVBK 20210128100655.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00894-015-2797-8 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2797-8 Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease [Elektronische Daten] [An Zhou, Jianping Hu, Lirong Wang, Guochen Zhong, Jian Pan, Zeyu Wu, Ailing Hui] Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q 2 = 0.552 and r 2 = 0.983 and an optimal CoMSIA model with q 2 = 0.581 and r 2 = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green). Springer-Verlag Berlin Heidelberg, 2015 Tacrine nationallicence 3D-QSAR nationallicence AChE inhibitor nationallicence Molecular dynamics nationallicence Alzheimer's disease nationallicence Zhou An Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut Hu Jianping Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, 15261, Pittsburgh, PA, USA aut Wang Lirong Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, 15261, Pittsburgh, PA, USA aut Zhong Guochen Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, 103 Meishan Road, 230038, Hefei, Anhui, China aut Pan Jian Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut Wu Zeyu Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut Hui Ailing Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-12 1610-2940 21:10<1 2015 21 894 https://doi.org/10.1007/s00894-015-2797-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2797-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zhou An Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut NATIONALLICENCE 700 1- Hu Jianping Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, 15261, Pittsburgh, PA, USA aut NATIONALLICENCE 700 1- Wang Lirong Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, 15261, Pittsburgh, PA, USA aut NATIONALLICENCE 700 1- Zhong Guochen Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, 103 Meishan Road, 230038, Hefei, Anhui, China aut NATIONALLICENCE 700 1- Pan Jian Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut NATIONALLICENCE 700 1- Wu Zeyu Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut NATIONALLICENCE 700 1- Hui Ailing Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, 230009, Hefei, Anhui, China aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-12 1610-2940 21:10<1 2015 21 894