Availableonlineatwww.sciencedirect.com EUROPEAN JOURNAL OF ° Science Direct MEDICINAL CHEMISTRY ELSEVIEI European Journal of Medicinal Chemistry 42(2007)977-984 http://www.elsevier.com/locate/ejmech Structure-based 3D-QSAR studies on heteroarylpiperazine derivatives as 5-ht3 receptor antagonists Ya-Ju Zhou, Li-Ping Zhu, Yun Tang D,, De-Yong Ye, *3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China Received 16 June 2006: received in revised form 13 December 2006: accepted 19 December 2006 Available online 13 January 2007 Abstract Structure-based 3D-QSAR studies were performed on a series of novel heteroarylpiperazine derivatives as 5-HT3 receptor antagonists with comparative molecular field analysis( CoMFA)and comparative molecular similarity indices analysis( CoMSIA)methods. The compounds were initially docked into the binding pocket of the homology model of 5-HT3 receptor using GOLD program. The docked conformations with the highest score were then extracted and used to build the 3D-QSAR models, with cross-validated r values 0.716 and 0. 762 for CoMFA and CoMSIA, respectively. The CoMFA and CoMSIA contour plots were also fitted into the 3D structural model of the receptor to identify the key interactions between them, which might be helpful for designing new potent 5-HT3 receptor antagonists. C 2007 Elsevier Masson SAS. All rights reserved Keywords: Structure-based 3D-QSAR: CoMFA: CoMSIA: 5-HT3 receptor 1. Introduction intrinsic channel activity of 5-HT3A. The subunit 5-HT3A is homo-oligomeric while 5-HT3B is heteromeric [2] 5-HT3 receptor is a prototypical member of the Cys-loop lectron microscope images of the purified 5-HT3 receptor ligand-gated ion channel (LGIC) superfamily, which also in- are available in the literature [3] but its three-dimensional (3D) cludes the glycine(Gly), type A Y-amino butyric acid(GA- structure has not yet been resolved at atomic level. However, BAA) and nicotinic acetylcholine(nACh)receptors. The ion the structure of Limnaea acetylcholine binding protein channel of 5-HT3 receptor is assembled with five subunits (AChBP) has been determined by X-ray crystallography re- and each subunit is thought to possess an N-terminal ligand cently, which is also a member of lGICs, and shares 20%o ho- binding domain, four transmembrane (TM) domains and mologous sequence with the extracellular domain of 5-HT a large intracellular loop connecting the third and fourth TM receptor [4]. Therefore, a homology model of the extracellular domains [1]. There are two main subtypes of 5-HT3 receptors: domain of human 5-HT3 receptor was built based on the crys- (1)5-HT3A, a neuronal receptor directly coupled to cation- tal structure of AChBP, and some known ligands were docked lective(Na*, K, Ca2, Mg+, and other ions)channels, into the binding site to validate the model [5]. During the pro- which has structural and functional similarity with the cess of our work, a similar study using a range of antagonists nACh, GABAA, Gly and other ligand-gated ion channels, was published, too [6] and(2)5-HT3B, a regulatory subunit able to modulate the ar study has long been used in elucidating mechanism of drug action and optimizing lead compound. When the 3D struc- Corresponding author. Tel: +86 21 64251052 ure of drug target is also available, structure-based drug design * Corresponding author. Tel: +86 21 54237559: fax: +86 21 64042268 methods can be combined with QSAR method, i.estructure- E-mailaddresses.ytang234@ecust.edu.cn(Y.Tang),dyye(@shmuedu based QSAR study, which could provide more information (D.-Y. Ye) for lead optimization. In this work, a new kind of 5-HT3 0223-5234/S- see front matter 2007 Elsevier Masson SAS. All rights reserved doi:10.1016/1 erech2006.12029Original article Structure-based 3D-QSAR studies on heteroarylpiperazine derivatives as 5-HT3 receptor antagonists Ya-Ju Zhou a , Li-Ping Zhu a , Yun Tang b, *, De-Yong Ye a, ** a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China b School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China Received 16 June 2006; received in revised form 13 December 2006; accepted 19 December 2006 Available online 13 January 2007 Abstract Structure-based 3D-QSAR studies were performed on a series of novel heteroarylpiperazine derivatives as 5-HT3 receptor antagonists with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The compounds were initially docked into the binding pocket of the homology model of 5-HT3 receptor using GOLD program. The docked conformations with the highest score were then extracted and used to build the 3D-QSAR models, with cross-validated r2 cv values 0.716 and 0.762 for CoMFA and CoMSIA, respectively. The CoMFA and CoMSIA contour plots were also fitted into the 3D structural model of the receptor to identify the key interactions between them, which might be helpful for designing new potent 5-HT3 receptor antagonists. 2007 Elsevier Masson SAS. All rights reserved. Keywords: Structure-based 3D-QSAR; CoMFA; CoMSIA; 5-HT3 receptor 1. Introduction 5-HT3 receptor is a prototypical member of the Cys-loop ligand-gated ion channel (LGIC) superfamily, which also in￾cludes the glycine (Gly), type A g-amino butyric acid (GA￾BAA) and nicotinic acetylcholine (nACh) receptors. The ion channel of 5-HT3 receptor is assembled with five subunits and each subunit is thought to possess an N-terminal ligand binding domain, four transmembrane (TM) domains and a large intracellular loop connecting the third and fourth TM domains [1]. There are two main subtypes of 5-HT3 receptors: (1) 5-HT3A, a neuronal receptor directly coupled to cation￾selective (Naþ, Kþ, Ca2þ, Mg2þ, and other ions) channels, which has structural and functional similarity with the nACh, GABAA, Gly and other ligand-gated ion channels, and (2) 5-HT3B, a regulatory subunit able to modulate the intrinsic channel activity of 5-HT3A. The subunit 5-HT3A is homo-oligomeric while 5-HT3B is heteromeric [2]. Electron microscope images of the purified 5-HT3 receptor are available in the literature [3] but its three-dimensional (3D) structure has not yet been resolved at atomic level. However, the structure of Limnaea acetylcholine binding protein (AChBP) has been determined by X-ray crystallography re￾cently, which is also a member of LGICs, and shares 20% ho￾mologous sequence with the extracellular domain of 5-HT3 receptor [4]. Therefore, a homology model of the extracellular domain of human 5-HT3 receptor was built based on the crys￾tal structure of AChBP, and some known ligands were docked into the binding site to validate the model [5]. During the pro￾cess of our work, a similar study using a range of antagonists was published, too [6]. QSAR study has long been used in elucidating mechanism of drug action and optimizing lead compound. When the 3D struc￾ture of drug target is also available, structure-based drug design methods can be combined with QSAR method, i.e. structure￾based QSAR study, which could provide more information for lead optimization. In this work, a new kind of 5-HT3 * Corresponding author. Tel.: þ86 21 64251052. ** Corresponding author. Tel.: þ86 21 54237559; fax: þ86 21 64042268. E-mail addresses: ytang234@ecust.edu.cn (Y. Tang), dyye@shmu.edu.cn (D.-Y. Ye). 0223-5234/$ - see front matter 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2006.12.029 European Journal of Medicinal Chemistry 42 (2007) 977e984 http://www.elsevier.com/locate/ejmech