In-vitro and in-silico analysis of neglected infectious disease compounds from an ADMET and ecotoxicology perspective

Summary 

Neglected infectious diseases (NIDs) are responsible of >500,000 deaths yearly and >billion people remain chronically injured or infected1. Leishmaniasis is a vector-borne NIDs caused by parasites, such as such as L. donovani and L. infantum. Dogs act as reservoir hosts, and then parasite is transmitted to humans by infected sand flies. Recently, resistance to classic therapies has emerged, and climate changes are causing an important geographical spread2. Another NID of concern is Zika Virus (ZV) infection, a vector-borne disease transmitted by mosquitos for which there are no specific or effective drugs3. 

Plant sourced substances are gaining attention in drug discovery for many pathologies and Punica granatum has beneficial effects against Leishmania and ZV models without toxicity4,5. Ellagic Acid (EA), a major constituent of pomegranate extracts, has antileishmanial activity on in vitro and in-vivo models6. Moreover, according to docking and molecular dynamics studies, EA is able to potently inhibit ZV NS3-helicase, which could explain pomegranate antiviral effect3. 

This STSM is based on a successful ongoing collaboration between the applicant institutions where many compound series designed and synthesized will undergo in-vitro and in-silico analysis from an ADMET and ecotoxicology perspective leading to datasets ready for publication. 

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Goals of the STSM 

Training: To begin with, training in in-vitro assay development, screening and ADMET profiling will be provided by researchers of the Host Institution. In addition, training will be provided in a variety of in-silico methods which is relevant to understanding the mechanism of action of active compounds in phenotypic assays. 

In-vitro ADMET profiling: At the Home Institution, natural products have been extracted from pomegranate with the EA and its metabolized Urolithins exhibiting antibacterial activity7,8. Among them, Urolithin A inhibits Leishmania proliferation9. The Home Institution has designed novel urolithin analogues with the aim of developing potent anti-infective agents. The synthesized compounds will be tested in the in-vitro ADMET assay panel developed at the Host Institution and the most optimal compounds progressed to in-vitro testing in a model of Leishmania and ZV to evaluate their antiparasitic and antiviral potential. 

In-silico compound annotation: Once the above data is generated for specific compounds, public databases will be interrogated and all biological data will be retrieved in order to provide insights into the mode of action of the compounds. This exercise will result in a knowledge graph for each compound series which will link compounds, druggable targets, in-vitro and in-vivo activities, ADMET, ecotoxicology and clinical data. 

Goals of the STSM 

Training: To begin with, training in in-vitro assay development, screening and ADMET profiling will be provided by researchers of the Host Institution. In addition, training will be provided in a variety of in-silico methods which is relevant to understanding the mechanism of action of active compounds in phenotypic assays. 

In-vitro ADMET profiling: At the Home Institution, natural products have been extracted from pomegranate with the EA and its metabolized Urolithins exhibiting antibacterial activity7,8. Among them, Urolithin A inhibits Leishmania proliferation9. The Home Institution has designed novel urolithin analogues with the aim of developing potent anti-infective agents. The synthesized compounds will be tested in the in-vitro ADMET assay panel developed at the Host Institution and the most optimal compounds progressed to in-vitro testing in a model of Leishmania and ZV to evaluate their antiparasitic and antiviral potential. 

In-silico compound annotation: Once the above data is generated for specific compounds, public databases will be interrogated and all biological data will be retrieved in order to provide insights into the mode of action of the compounds. This exercise will result in a knowledge graph for each compound series which will link compounds, druggable targets, in-vitro and in-vivo activities, ADMET, ecotoxicology and clinical data. 

Goals of the STSM 

Training: To begin with, training in in-vitro assay development, screening and ADMET profiling will be provided by researchers of the Host Institution. In addition, training will be provided in a variety of in-silico methods which is relevant to understanding the mechanism of action of active compounds in phenotypic assays. 

In-vitro ADMET profiling: At the Home Institution, natural products have been extracted from pomegranate with the EA and its metabolized Urolithins exhibiting antibacterial activity7,8. Among them, Urolithin A inhibits Leishmania proliferation9. The Home Institution has designed novel urolithin analogues with the aim of developing potent anti-infective agents. The synthesized compounds will be tested in the in-vitro ADMET assay panel developed at the Host Institution and the most optimal compounds progressed to in-vitro testing in a model of Leishmania and ZV to evaluate their antiparasitic and antiviral potential. 

In-silico compound annotation: Once the above data is generated for specific compounds, public databases will be interrogated and all biological data will be retrieved in order to provide insights into the mode of action of the compounds. This exercise will result in a knowledge graph for each compound series which will link compounds, druggable targets, in-vitro and in-vivo activities, ADMET, ecotoxicology and clinical data.