J Mol model(2006)12:390-397 DOI10.1007/s008940050058y ORIGINAL PAPER Qiong Xie. Yun Tang. Wei Li Xing-Hai Wang Zhui-Bai Qiu Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method Received: 8 December 2004/ Accepted: 9 August 2005/ Published online: 11 January 2006 c) Springer-Verlag 2006 Abstract Molecular docking has been performed to Introduction investigate the binding mode of (-)-meptazinol (MEP) with acetylcholinesterase(AChE) and to screen bis- Alzheimers disease(AD)is a neurodegenerative disorder meptazinol(bis- MEP)derivatives for preferable synthetic that seriously threatens the health of elderly people around candidates virtually. A reliable and practical docking the world. Although with an unclear pathogenesis, AD is method for investigation of AChE ligands was established commonly believed to be associated with the dysfunction by the comparison of two widely used docking programs, of the central cholinergic system [1, 2]. Acetylcholinester- FlexX and GOLD. In our hands, we had more luck using ase (AChE) plays a key role in the regulation of the GOLd than FlexX in reproducing the experimental poses cholinergic system, and hence, inhibition of AChE has of known ligands(RMSD<1.5 A). GOLD fitness values of emerged as one of the most promising strategies for the known ligands were also in good agreement with their treatment of AD. So far, four AChE inhibitors have been activities In the present GOLd docking protocol, (-)-MEP approved by the FDa in the US for treatment of AD, seemed to bind with the enzyme catalytic site in an open- namely tacrine (THA)[3], donepezil (E2020)[4],rivas- gate conformation through strong hydrophobic interactions tigmine [5] and galanthamine(GNT)[6]. In China(-)- and a hydrogen bond. Virtual screening of a potential Huperzine A(HUPA)[7] was also approved for the same candidate compound library suggested that the most purpose. Due to drawbacks such as hepatotoxicity and low deni rising 15 bis-mEP derivatives on the list were mainly selectivity as in the case of tacrine [8], the search for new derived from(-)-MEP with conformations of(,S)and AChE inhibitors with high selectivity and low toxicity SR, RS)and with a 2-to 7-carbon linkage. Although there remains an urgent task are still no biological results to confirm the predictive Meptazinol (MEP, Fig. 1)is a potent opioid analgesic but power of this method, the current study could provide an with less respiratory depression and low addiction liability altermate tool for structural optimization of()-MEP as new [9], possibly due to a component of cholinergic activation AChE inhibitors presented in its pharmacological profile [10]. Early in 1986 Ennis et al. reported the inhibition of AChe by meptazinol Keywords Meptazinol (MEP) Molecular docking [ll], which not only confirmed MEP's involvement in the GOLD Acetylcholinesterase(AChE) cholinergic system, but also opened a door in the search for new AChE inhibitors. Ennis'experiments demonstrated that (+)-MEP acted on AChE in vitro with an ICso of 6. 4 uM, while the (r-enantiomer (IC50=3. 3 HM) was far more potent than its antipole (+)-enantiomer(ICso>1.0 mM). The Q.Xie.Y.Tang(凶)·W.Li·X.H.Wang:Z.B.Qu() inhibitory potency of(-)-MEp was almost equivalent to that School of Pharmacy, Fudan University of ()-galanthamine and tacrine, about 100 times less potent hanghai, 200032, People's Republic of china than physostigmine [11]. Recently, we determined the 54237419 absolute configurations of ()and (+)-MEP as S and R, respectively, by X-ray crystal structures(Fig. 1)[12] Tel:+86-21-54237595 Therefore, it was of considerable interest to investigate the mechanism of action of (-)-MEP on AChE for the search of Y Tang() hool of Pharmacy new mep derivatives as achE inhibitors East China University of Science and Technology, Molecular docking is an efficient tool for investigating Shanghai, 200237, People's Republic of China receptor-ligand interactions and for virtual screening Tel:+86-21-64251052 which plays a key role in rational drug design [13J Mol Model (2006) 12: 390–397 DOI 10.1007/s00894-005-0058-y OR IG INAL PAPER Qiong Xie . Yun Tang . Wei Li . Xing-Hai Wang . Zhui-Bai Qiu Investigation of the binding mode of (−)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method Received: 8 December 2004 / Accepted: 9 August 2005 / Published online: 11 January 2006 # Springer-Verlag 2006 Abstract Molecular docking has been performed to investigate the binding mode of (−)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis￾meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.5 Å). GOLD fitness values of known ligands were also in good agreement with their activities. In the present GOLD docking protocol, (−)-MEP seemed to bind with the enzyme catalytic site in an open￾gate conformation through strong hydrophobic interactions and a hydrogen bond. Virtual screening of a potential candidate compound library suggested that the most promising 15 bis-MEP derivatives on the list were mainly derived from (−)-MEP with conformations of (S,S) and (SR,RS) and with a 2- to 7-carbon linkage. Although there are still no biological results to confirm the predictive power of this method, the current study could provide an alternate tool for structural optimization of (−)-MEP as new AChE inhibitors. Keywords Meptazinol (MEP) . Molecular docking . GOLD . Acetylcholinesterase (AChE) Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that seriously threatens the health of elderly people around the world. Although with an unclear pathogenesis, AD is commonly believed to be associated with the dysfunction of the central cholinergic system [1, 2]. Acetylcholinester￾ase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. So far, four AChE inhibitors have been approved by the FDA in the US for treatment of AD, namely tacrine (THA) [3], donepezil (E2020) [4], rivas￾tigmine [5] and galanthamine (GNT) [6]. In China (−)- Huperzine A (HUPA) [7] was also approved for the same purpose. Due to drawbacks such as hepatotoxicity and low selectivity as in the case of tacrine [8], the search for new AChE inhibitors with high selectivity and low toxicity remains an urgent task. Meptazinol (MEP, Fig. 1) is a potent opioid analgesic but with less respiratory depression and low addiction liability [9], possibly due to a component of cholinergic activation presented in its pharmacological profile [10]. Early in 1986 Ennis et al. reported the inhibition of AChE by meptazinol [11], which not only confirmed MEP’s involvement in the cholinergic system, but also opened a door in the search for new AChE inhibitors. Ennis’ experiments demonstrated that (±)-MEP acted on AChE in vitro with an IC50 of 6.4 μM, while the (−)-enantiomer (IC50=3.3 μM) was far more potent than its antipole (+)-enantiomer (IC50>1.0 mM). The inhibitory potency of (−)-MEP was almost equivalent to that of (−)-galanthamine and tacrine, about 100 times less potent than physostigmine [11]. Recently, we determined the absolute configurations of (−) and (+)-MEP as S and R, respectively, by X-ray crystal structures (Fig. 1) [12]. Therefore, it was of considerable interest to investigate the mechanism of action of (−)-MEP on AChE for the search of new MEP derivatives as AChE inhibitors. Molecular docking is an efficient tool for investigating receptor-ligand interactions and for virtual screening, which plays a key role in rational drug design [13, 14], Q. Xie . Y. Tang (*) . W. Li . X.-H. Wang . Z.-B. Qiu (*) School of Pharmacy, Fudan University, Shanghai, 200032, People’s Republic of China e-mail: ytang234@yahoo.com.cn Tel.: +86-21-54237419 e-mail: zbqiu@shmu.edu.cn Tel.: +86-21-54237595 Y. Tang (*) School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People’s Republic of China Tel.: +86-21-64251052