Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds
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, a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-03-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcimb.2020.00118/full |
| _version_ | 1818598392325996544 |
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| author | Congshan Liu Jianhai Yin Jiaqing Yao Zhijian Xu Yi Tao Haobing Zhang |
| author_facet | Congshan Liu Jianhai Yin Jiaqing Yao Zhijian Xu Yi Tao Haobing Zhang |
| author_sort | Congshan Liu |
| collection | DOAJ |
| description | 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 Cmax 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. |
| first_indexed | 2024-12-16T12:02:58Z |
| format | Article |
| id | doaj.art-f2d74d51336c4ac793d0a8c27e8d7e55 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-16T12:02:58Z |
| publishDate | 2020-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-f2d74d51336c4ac793d0a8c27e8d7e552022-12-21T22:32:24ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882020-03-011010.3389/fcimb.2020.00118509328Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal CompoundsCongshan Liu0Jianhai Yin1Jiaqing Yao2Zhijian Xu3Yi Tao4Haobing Zhang5Key Laboratory of Parasite and Vector Biology, Chinese Center for Disease Control and Prevention, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, MOH, Shanghai, ChinaKey Laboratory of Parasite and Vector Biology, Chinese Center for Disease Control and Prevention, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, MOH, Shanghai, ChinaKey Laboratory of Parasite and Vector Biology, Chinese Center for Disease Control and Prevention, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, MOH, Shanghai, ChinaDrug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaKey Laboratory of Parasite and Vector Biology, Chinese Center for Disease Control and Prevention, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, MOH, Shanghai, ChinaKey Laboratory of Parasite and Vector Biology, Chinese Center for Disease Control and Prevention, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, MOH, Shanghai, ChinaEchinococcosis 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 Cmax 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.https://www.frontiersin.org/article/10.3389/fcimb.2020.00118/fullechinococcosisEchinococcus multilocularispharmacophore modelingvirtual screeningsin vitro drug screencytotoxicity |
| spellingShingle | Congshan Liu Jianhai Yin Jiaqing Yao Zhijian Xu Yi Tao Haobing Zhang Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds Frontiers in Cellular and Infection Microbiology echinococcosis Echinococcus multilocularis pharmacophore modeling virtual screenings in vitro drug screen cytotoxicity |
| title | Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds |
| title_full | Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds |
| title_fullStr | Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds |
| title_full_unstemmed | Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds |
| title_short | Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds |
| title_sort | pharmacophore based virtual screening toward the discovery of novel anti echinococcal compounds |
| topic | echinococcosis Echinococcus multilocularis pharmacophore modeling virtual screenings in vitro drug screen cytotoxicity |
| url | https://www.frontiersin.org/article/10.3389/fcimb.2020.00118/full |
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