title: 3D-QSAR studies on thiazolidin-4-one S1P₁receptor agonists by CoMFA and CoMSIA.
abstract: Selective S1P(1) receptor agonists have therapeutic potential to treat a variety of immune-mediated diseases. A series of 2-imino-thiazolidin-4-one derivatives displaying potent S1P(1) receptor agonistic activity were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q(2) value of 0.751 and an r(2) value of 0.973, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic, hydrophobic and H-bond donor descriptors, predicted a q(2) value of 0.739 and an r(2) value of 0.923. The models were graphically interpreted using contour plots which gave more insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active S1P(1) receptor agonists.
authors.affiliation: College of Biology Science and Technology, Jinan University, Guangzhou 510632, China; E-Mails:  litmony@sohu.com  (C.Q.);  thuangli@jnu.edu.cn  (L.H.).
authors.forename: Chuiwen
authors.initials: C
authors.lastname: Qian
authors.forename: Junxia
authors.initials: J
authors.lastname: Zheng
authors.forename: Gaokeng
authors.initials: G
authors.lastname: Xiao
authors.forename: Jialiang
authors.initials: J
authors.lastname: Guo
authors.forename: Zhaoqi
authors.initials: Z
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
authors.forename: Longyi
authors.initials: L
authors.lastname: Rao
authors.forename: Pinghua
authors.initials: P
authors.lastname: Sun
mesh_terms: D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D021281:Quantitative Structure-Activity Relationship; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D055672:Static Electricity; D053778:Thiazolidines / Q000737:chemistry*
chemical_list: D049349:Receptors, Lysosphingolipid; D053778:Thiazolidines
references.citation: J Med Chem. 1995 Mar 31;38(7):1060-6
references.pmid: 7707309
references.citation: J Am Chem Soc. 1988 Aug 1;110(18):5959-67
references.pmid: 22148765
references.citation: Prog Clin Biol Res. 1989;291:161-5
references.pmid: 2726839
references.citation: Bioorg Med Chem. 2008 Sep 1;16(17):8042-53
references.pmid: 18701298
references.citation: Mol Pharmacol. 2000 Aug;58(2):449-54
references.pmid: 10908314
references.citation: Am J Transplant. 2005 Mar;5(3):529-36
references.pmid: 15707407
references.citation: J Comput Aided Mol Des. 2004 Jul-Sep;18(7-9):563-76
references.pmid: 15729855
references.citation: Nature. 2004 Jan 22;427(6972):355-60
references.pmid: 14737169
references.citation: J Biol Chem. 2004 Apr 2;279(14):13839-48
references.pmid: 14732717
references.citation: Biochim Biophys Acta. 2006 Dec;1758(12):2016-26
references.pmid: 16996023
references.citation: J Mol Graph Model. 2002 Jan;20(4):269-76
references.pmid: 11858635
references.citation: Bioorg Med Chem Lett. 2004 Jun 21;14(12):3351-5
references.pmid: 15149705
references.citation: J Mol Graph Model. 2009 Feb;27(6):735-43
references.pmid: 19117780
references.citation: J Biol Chem. 2004 Apr 9;279(15):15396-401
references.pmid: 14732704
references.citation: J Med Chem. 1994 Nov 25;37(24):4130-46
references.pmid: 7990113
references.citation: J Med Chem. 2010 May 27;53(10):4198-211
references.pmid: 20446681
references.citation: Eur J Med Chem. 2010 Apr;45(4):1560-71
references.pmid: 20153089
references.citation: Annu Rev Biochem. 2004;73:321-54
references.pmid: 15189145
references.citation: J Environ Sci Health B. 2008 May;43(4):281-7
references.pmid: 18437614
references.citation: J Comput Aided Mol Des. 1999 Jan;13(1):1-10
references.pmid: 10087495
references.citation: J Chem Inf Comput Sci. 1997 Mar-Apr;37(2):392-401
references.pmid: 9090857
references.citation: Prog Lipid Res. 2007 Mar;46(2):126-44
references.pmid: 17449104
references.citation: J Pharmacol Exp Ther. 2004 May;309(2):758-68
references.pmid: 14747617
references.citation: Nat Rev Mol Cell Biol. 2003 May;4(5):397-407
references.pmid: 12728273
references.citation: Cancer Chemother Rep. 1972 Aug;56(4):443-56
references.pmid: 5081587
references.citation: Pharmacol Rev. 2002 Jun;54(2):265-9
references.pmid: 12037142
references.citation: Annu Rev Biochem. 2009;78:743-68
references.pmid: 19231986
references.citation: J Comput Aided Mol Des. 1993 Oct;7(5):587-619
references.pmid: 8294948
references.citation: Trends Mol Med. 2006 Feb;12(2):65-75
references.pmid: 16406843