Vol.:(0123456789) 1 3 Journal of Computer-Aided Molecular Design https://doi.org/10.1007/s10822-019-00230-y Repurposing of known drugs for leishmaniasis treatment using bioinformatic predictions, in vitro validations and pharmacokinetic simulations Christian Bustamante 1  · Rodrigo Ochoa 1,2  · Claudia Asela 1  · Carlos Muskus 1 Received: 13 May 2019 / Accepted: 28 September 2019 © Springer Nature Switzerland AG 2019 Abstract Leishmaniasis is a neglected tropical disease caused by Leishmania parasites and is associated to more than 1.3 million cases annually. Some of the pharmacological options for treating the disease are pentavalent antimonials, pentamidine, miltefos- ine, and amphotericin B. However, all are associated with a wide range of adverse effects and contraindications, as well as resistance from the parasite. In the present study, we looked for pharmacological alternatives to treat leishmaniasis, with a focus on drug repurposing. This was done by detecting potential homologs between proteins targeted by approved drugs and proteins of the parasite. The proteins were analyzed using an interaction network, and the drugs were subjected to in vitro evaluations and pharmacokinetics simulations to compare probable plasma concentrations with the effective concentrations detected experimentally. This strategy yielded a list of 33 drugs with potential anti-Leishmania activity, and more than 80 possible protein targets in the parasite. From the drugs tested, two reported high in vitro activity (perphenazine EC 50 = 1.2 µg/ mL and rifabutin EC 50 = 8.5 µg/mL). These results allowed us to propose these drugs as candidates for further in vivo studies and evaluations of the effectiveness on their topical forms. Keywords Drug repurposing · Pharmacokinetic simulations · Leishmaniasis · Protein interaction networks · In vitro activity Introduction Leishmaniasis is a disease caused by Leishmania parasites and is transmitted to humans through bites of phlebotomine insects of the genera Phlebotomus in the Old World and Lutzomyia in the New World. The World Health Organiza- tion (WHO) classifies leishmaniasis as a neglected tropical disease, which mainly affects the low-income population of developing countries [1]. Leishmaniasis is endemic in 98 countries around the world, and more than 1.3 million new cases are reported annually, of which 20,000 to 30,000 are fatal [1, 2]. The first pharmacological choice to treat the disease are the pentavalent antimonials, available in two forms: meglumine antimoniate (Glucantime®), and sodium sti- bogluconate (Pentostam®). Other drugs used to treat this disease include amphotericin B, miltefosine, pentamidine, paromomycin, and sitamaquine [3, 4]. Despite these thera- peutic options, pharmacological treatment of leishmaniasis is not completely satisfactory. Almost all these drugs cause adverse reactions or are contraindicated in various condi- tions, such as pregnancy and heart, liver, or kidney prob- lems. In addition, there are reports of the parasite acquiring resistance to several of these drugs [5]. To overcome the mentioned challenges, one approach available is drug repurposing, which involves predicting second uses of known drugs that are used for a different purpose. This approach, in contrast to the de novo discovery of new molecules, does not require of very large economic Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-019-00230-y) contains supplementary material, which is available to authorized users. * Carlos Muskus carlos.muskus@udea.edu.co 1 Programa de Estudio y Control de Enfermedades Tropicales-PECET, Faculty of Medicine, University of Antioquia, Medellin, Colombia 2 Present Address: Biophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia, Medellin, Colombia