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

• Published in: Frontiers in cellular and infection microbiology Vol. 10; p. 118
• Main Authors: Liu, Congshan, Yin, Jianhai, Yao, Jiaqing, Xu, Zhijian, Tao, Yi, Zhang, Haobing
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 20.03.2020
• Subjects: Cellular and Infection Microbiology; cytotoxicity; echinococcosis; Echinococcus multilocularis; in vitro drug screen; pharmacophore modeling; virtual screenings; in vitro drug screen; Echinococcus multilocularis; pharmacokinetics analysis; echinococcosis; pharmacophore modeling; virtual screenings; E. multilocularis-infected mice; cytotoxicity
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2020.00118

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 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 pharmacodynamic and pharmacokinetic studies. At the two tested doses (50 and 25 mg/kg), S6 inhibited the growth of 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 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 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.