Ai-lin LIU,Wen-wen LIAN,Xiao-cong PANG,Wei ZHOU,Jian-song FANG,Guan-hua DU

(Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

T1-19

DL0410,a candidate for anti-Alzheimer disease with multiple targets in multiple pathways

Ai-lin LIU,Wen-wen LIAN,Xiao-cong PANG,Wei ZHOU,Jian-song FANG,Guan-hua DU

(Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

OBJECTIVETo find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODSA series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease(AD)using the multitargetquantitative structure-activity relationships(mt-QSAR)method.While drug screening assays were established to evaluate the predicted active molecules.In addition,various cellular models and animal models related with AD were set up to further study the effects of the active compounds.RESULTSA system for the discovery of Multitarget-Directed Ligands against AD was set up and applied,the predicted active compounds were validated by the drug screening assays,and several active compounds with multiple targets were discovered.Among them,DL0410 exerted high activity on H3R,α7nAChR,AChE and ERα,also displayed the most significant effect in improving the ability of memory and learning in several AD animal models.The study on its action mechanisms showed that it′s effect may partially through increasing neurotransmitter,inhibiting oxidative emergency,inhibiting the expression of APP,and promoting long-term potentiation.Besides,DL0410 is of more safety than the first-line clinical medicines.CONCLUSIONDL0410 is a promising candidate for further development for AD treatment.

DL0410;Alzheimer disease;multiple targets;multiple pathways

The project supported by National Great Science and Technology Projects(2014ZX09507003-002,2013ZX09402203 and 2013ZX09508104001002),CAMS Initiative for Innovative Medicine(CAMS-I2M)(2016-I2M-3-007);and National Natural Science Foundation of China(81673480)

Guan-hua DU,Tel:(010)63165184,E-mail:dugh@imm.ac.cn;Ai-lin LIU,Tel:(010)83150885,E-mail:liuailin@imm.ac.cn