River blindness is a neglected tropical disease caused by the parasitic nematode Onchoverca volvulus. It affects more than 37 million people worldwide especially in developing countries. Currently, the only approved drug for treating river blindness is ivermectin, which is a broad-spectrum antiparasitic agent. However, signs of resistance towards ivermectin have started to emerge. As a result, there is an urgent need for the development of new therapeutic agents. Different studies have shown that OvCHT1, a larval-specific chitinase, is involved in the nematode development and could represent a potential therapeutic target for river blindness. Over the years, the Janda’s group at Scripps identified closantel as a potent, micro-molar and specific inhibitor of OvCHT1, and later synthetized and tested more than 50 closantel analogues with experimental pIC50 ranging from 3.7 to 6.4. In this study, we investigated the chemical space of the aforementioned set of closantel analogues. Notably, we used (i) 2D structural descriptors to cluster all analogues and identify structure-activity relationships, (ii) molecular docking to evaluate the docking scores of all analogues in the OvCHT1 binding site and identify key OvCHT1-inhibitor interactions, and (iii) molecular dynamics simulations to study of the flexibility of the OvCHT1-inhibitor complexes and in particular the dynamic aspect of each OvCHT1-inhibitor molecular interaction. Finally, we designed several new analogues and screened the ZINC database to identified chemicals with potentially improved OvCHT1 inhibition potencies.

Cheminformatics modeling of closantel analogues potentially relevant for creating river blindness

253rd National Meeting (2017)

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