39 24 1 1 1 2 1* 1. 1001022. 100191 HMG-CoA PPAR-α HMG-CoA PPAR-α PPAR-α PPAR-α 8 - DS Receptor-Ligand Pharmacophore Generation Screen Library 2 3 19 N 2. 82 CAI 1. 84 TCMD 5 235 1 193 62 38 7 poproteinlipase LPL TG LDL-C HDL-C 3 4-5 HMG-CoA 6 1 - LDL-C HDL-C - 2 HMG-CoA 7 αperoxisome proliferator receptor-alpha PPAR-α li- 8 PDB Protein Data Bank PPAR-α 2014-04-04-2011ZX09401-028 BJGJ1412 81173522 * Tel 01084738620 E-mailcollean_zhang@ 163. com 4839
39 24 world traditional medicine patent database WTM PPAR-α HMG-CoA 1 ~ 4 1 1. 1 PDB PPAR-α CAI comprehensive appraisal index 10-11 CAI N A 8-1 367 98 The Binding Database http/ /www. bindingdb. org /bind /index. jsp A% = H a 100% A PPAR-α 269 MDDR MDL Drug Data ReportVersion 2007. 2 CAI = N N = H a /H t A /D = H a D H t A A% N N A% N A% Y% = H a 100% H t 1 2 3 4 1. 4 traditional Chinese medi- 1 PDB PPAR-α cine database TCMD version 2009 2 Table 1 The information of the ligand-receptor complexes of Best PPAR-α from PDB / IC 50 /nmol L - 1 Search 3KDU NKS 2. 07 347 3KDT 7HA 2. 70 260 1K7L 544 2. 50-2NPA MMB 2. 30-2P54 735 1. 79-6 2ZNN S44 2. 01-3FEI CTM 2. 40 20 1. 5 3VI8 13M 1. 75-1. 2 DSDiscovery Studio 4. 0Receptor-Ligand Pharmacophore Generation - 2 Screen Library 2. 1 DS Receptor-Ligand Pharmacophore Generation 1. 3 - H a H t A Screen D Library Screen A% N A% Library 4840
39 24 4 ~ 7 468 2 2. 2 CAI 10 2 10 hydrogen bond acceptor A hydrophobic region H 1 1 excluded volumes EV3 N Fig. 1 The first pharmacophore 1 3 4 6 7 9 N 3 CAI 1 CAI 3 Table 3 The result of the traditional Chinese medicine from virtual screening 1 1 39 9 2 CAI 10 34 8 Table 2 The CAI top ten pharmacophores based on the structure 32 8 of conjugates 33 8 25 8 No. N CAI 24 8 1 H2 A5 H6 A7 H9 2ZNN 2. 82 1. 84 21 8 2 H2 A3 H4 H5 A6 1K7L 2. 52 1. 70 19 8 3 A1 H2 A3 H5 H7 1K7L 2. 90 1. 63 18 8 4 H2 H5 A6 H7 A12 2P54 2. 90 1. 63 17 7 5 A1 H2 A3 H4 H5 1K7L 2. 41 1. 55 17 7 6 A1 H4 H5 A6 H7 2P54 3. 50 1. 50 16 7 7 A1 H2 H3 A6 H8 H11 3VI8 3. 57 1. 46 16 7 8 H2 H5 A6 H7 A8 2NPA 2. 65 1. 43 14 7 9 H2 A3 H5 A6 H7 1K7L 2. 98 1. 43 14 7 10 H1 A5 A7 H9 A10 2ZNN 2. 45 1. 43 14 7 A. H. 13 6 2. 3 DS 12 6 12 6 5 235 1 11 6 10 6 10 6 10 6 10 6 9 6 2 673 9 6 1 193 2. 4 6 81 62 3 13 6 13 6 4841
39 24 12 2 42 48 14 4 4 Table 4 The result of patent search 6 1 5 1 3 1 3 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3 12- β- 7 7 12 19 13 10 - PPAR-α 2 PPAR-α 14 NO 16 obovatol A- ACAT 17 7 18 8-5 7 3' 4' - cis-9 cis-12- cis-9 2 TG TC 15 4842
39 24 10. J. 1. J. 201017. 20044 58. 11Lin S K. Pharmacophore perception development and use in drug 2. J. J. Molecules2000 5987. 2013 191 7. 12. S. 2010. 3. J. 13. J. 2007 201197 539. 485392. 4. J. 14. 40 J. 2011 20151396. 2007 16304448. 5. 15. J. J. 2002 161. 2004 254 235. 6Yang J. Application of computer-aided drug design to traditional 16. Chinese medicine J. Int J Org Chem201331. J. 7Yang HShen YChen Jet al. Structure-based virtual screening for identification of novel 11β-HSD1 inhibitorsj. Eur J 17. J. Med Chem2009443 1167. 2012 37233526. 2002 8143. 8. 18. J. J. 2008 101 22. 2013169. 9. PDE4B 19. J. J. 2012 1451996. 2005 172 160. Study on lipid-lowering traditional Chinese medicines based on pharmacophore technology and patent retrieval HUO Xiao-qian 1 HE Yu-su 1 QIAO Lian-sheng 1 SUN Zhi-yi 2 ZHANG Yan-ling 1* 1. Traditional Chinese Medicine Information Engineering Research CenterBeijing University of Chinese MedicineBeijing 100102China 2. Beijing Eastlinden Science & Technology Co. Ltd. Beijing 100191China AbstractThe combined application of statins that inhibit HMG-CoA reductase and fibrates that activate PPAR-α can produce a better lipid-lowering effect than the simple applicationbut with stronger adverse reactions at the same time. In the treatment of hyperlipidemia the combined administration of TCMs and HMG-CoA reductase inhibitor in treating hyperlipidemia shows stable efficacy and less adverse reactionsand provides a new option for the combined application of drugs. In this article the pharmacophore technology was used to search chemical components of TCMs trace their source herbsand determine the potential common TCMs that could activate PPAR-α. Because there is no hyperlipidemia-related medication reference in modern TCM classicsto ensure the high safety and efficacy of all selected TCMswe selected TCMs that are proved to be combined with statins in the World Traditional /Natural Medicine Patent Databaseanalyzed corresponding drugs in pharmacophore results based on thatand finally obtained common TCMs that can be applied in PPAR-α and combined with statins. Specifically the pharmacophore model was based on eight receptor-ligand complexes of PPAR-α. The Receptor-Ligand Pharmacophore Generation module in the DS program was used to build the modeloptimize with the Screen Library moduleand get the best sub-pharmacophorewhich consisted of two hydrogen bond acceptor three hydrophobic groups and 19 excluded volumeswith the identification effectiveness index value N of 2. 82 and the comprehensive evaluation index CAI value of 1. 84. The model was used to screen the TCMD databasehit 5 235 kinds of chemical components and 1 193 natural animals and plantsand finally determine 62 TCMs. Through patent retrievalwe found 38 TCMsAfter comparing with the virtual screening resultswe finally got seven TCMs. Key wordslipid-loweringpharmacophorevirtual screeningpatent searchfibratesdrug combination doi10. 4268 /cjcmm20142427 4843