Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds

doi:10.3389/fcimb.2020.00118

	Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds
	Liu, Congshan 1; Yin, Jianhai 1; Yao, Jiaqing 1; Xu, Zhijian 2; Tao, Yi 1; Zhang, Haobing 1
刊名	FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
	2020-03-20
卷号	10 页码:12
关键词	echinococcosis Echinococcus multilocularis pharmacophore modeling virtual screenings in vitro drug screen cytotoxicity E multilocularis-infected mice pharmacokinetics analysis
ISSN号	2235-2988
DOI	10.3389/fcimb.2020.00118
通讯作者	Tao, Yi(Taoyi_NIPD@163.com) ; Zhang, Haobing(zhanghaobing2@163.com)
英文摘要	Echinococcosis is a serious helminthic zoonosis with a great impact on human health and livestock husbandry. However, the clinically used drugs (benzimidazoles) have a low cure rate, so alternative drugs are urgently needed. Currently, drug screenings for echinococcosis are mainly phenotype-based, and the efficiency of identifying active compounds is very low. With a pharmacophore model generated from the structures of active amino alcohols, we performed a virtual screening to discover novel compounds with anti-echinococcal activity. Sixty-two compounds from the virtual screening were tested on Echinococcus multilocularis protoscoleces, and 10 of these compounds were found to be active. After further evaluation of their cytotoxicity, S6 was selected along with two active amino alcohols for in vivo pharmacodynamic and pharmacokinetic studies. At the two tested doses (50 and 25 mg/kg), S6 inhibited the growth of E. multilocularis in mice (14.43 and 9.53%), but no significant difference between the treatment groups and control group was observed. Treatment with BTB4 and HT3 was shown to be ineffective. During the 28 days of treatment, the death of mice in the mebendazole, HT3, and BTB4 groups indicated their toxicity. The plasma concentration of S6 administered by both methods was very low, with the C-max being only 1 ng/ml after oral administration and below the detection limit after intramuscular administration. In addition, the plasma concentrations of BTB4 and HT3 in vitro did not reach high enough levels to kill the parasites. The toxicities of these two amino alcohols indicated that they are not suitable for further development as anti-echinococcal drugs. However, further attempts should be made to increase the bioavailability of S6 and modify its structure. In this study, we demonstrate that pharmacophore-based virtual screenings with high drug identification efficiency could be used to find novel drugs for treating echinococcosis.
资助项目	National Natural Science Foundation of China[81401691] ; National Natural Science Foundation of China[81702030]
WOS关键词	MULTICENTER CLINICAL-TRIALS ; IN-VIVO ; ANTIMALARIAL AGENTS ; MOLECULAR DOCKING ; IDENTIFICATION ; INHIBITORS ; DESIGN ; DERIVATIVES ; MEFLOQUINE ; VITRO
WOS研究方向	Immunology ; Microbiology
语种	英语
出版者	FRONTIERS MEDIA SA
WOS记录号	WOS:000525510900001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281078]
专题	中国科学院上海药物研究所
通讯作者	Tao, Yi; Zhang, Haobing
作者单位	1.MOH, Natl Ctr Int Res Trop Dis, WHO Collaborating Ctr Trop Dis,Natl Inst Parasit, Key Lab Parasite & Vector Biol,Chinese Ctr Dis Co, Shanghai, Peoples R China 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Liu, Congshan,Yin, Jianhai,Yao, Jiaqing,et al. Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds[J]. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY,2020,10:12.
APA	Liu, Congshan,Yin, Jianhai,Yao, Jiaqing,Xu, Zhijian,Tao, Yi,&Zhang, Haobing.(2020).Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds.FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY,10,12.
MLA	Liu, Congshan,et al."Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds".FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY 10(2020):12.