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Virtual screening and optimization of typeⅡ inhibitors of JAK2 from a natural product library

中国药理学与毒理学杂志 2015年第S1期29卷 98-99页

作者： Dik-LungMA DanielShiu-HinCHAN GuoWEI Hai-jingZHONG HuiYANG LaiToLEUNG ElizabethA.GULLEN PaulineChIU Yung-ChiCHENG Chung-hangLEUNG Department of Chemistry Hong Kong Baptist University Hong Kong China Department of Chemistry and the State Key Laboratory of Synthetic Chemistry University of Hong Kong Hong Kong China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA

OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of JAK2 using the DOLPHIN protocol.METHODS Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of JAK2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in silico.The novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for JAK2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral activity.RESULTS The top eleven highest-scoring compounds were generated from the initial high-throughput virtual screening.Amentoflavone 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological evaluation.In dose-response experiments,amentoflavone 1ainhibited JAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·L-1.As a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of 1a.The octyl(C8)analogue 1bdisplayed superior potency against JAK2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this study.Moreover,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of JAK2.CONCLUSION Amentoflavone 1ahas been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library.In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo.Molecular modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of JAK2.

关键词： JAK2 natural products virtual screening structure-

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