Computer-Assisted Discovery of Alkaloids with Schistosomicidal Activity

Abstract

Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma; it is commonly caused by Schistosoma mansoni, which is transmitted by Bioamphalaria snails. Studies show that more than 200 million people are infected and that more than 90% of them live in Africa. Treatment with praziquantel has the best cost–benefit result on the market. However, hypersensitivity, allergy, and drug resistance are frequently presented after administration. From this perspective, ligand-based and structure-based virtual screening (VS) techniques were combined to select potentially active alkaloids against S. mansoni from an internal dataset (SistematX). A set of molecules with known activity against S. mansoni was selected from the ChEMBL database to create two different models with accuracy greater than 84%, enabling ligand-based VS of the alkaloid bank. Subsequently, structure-based VS was performed through molecular docking using four targets of the parasite. Finally, five consensus hits (i.e., five alkaloids with schistosomicidal potential), were selected. In addition, in silico evaluations of the metabolism, toxicity, and drug-like profile of these five selected alkaloids were carried out. Two of them, namely, 11,12-methylethylenedioxypropoxy and methyl-3-oxo-12-methoxy-n(1)-decarbomethoxy-14,15-didehydrochanofruticosinate, had plausible toxicity, metabolomics, and toxicity profiles. These two alkaloids could serve as starting points for the development of new schistosomicidal compounds based on natural products.

Virtual Screening Based on Ligand and Structure with in vitro Assessment of Neolignans against Trypanosoma cruzi

“…Descriptors were selected and modeled following a 5-fold external cross validation procedure using the random forest algorithm (RF). [37][38][39] The 5-fold external validation technique used in this work is a technique that the entire data set is partitioned five times into a modeling set (training set) including 80% of the compounds the set, and the external cross validation data set, comprising the remaining 20% of the compounds the data set. [37][38][39] After this, only the modeling set is used to build the models and then the models are validated with the external cross validation technique.…”

“…[37][38][39] The 5-fold external validation technique used in this work is a technique that the entire data set is partitioned five times into a modeling set (training set) including 80% of the compounds the set, and the external cross validation data set, comprising the remaining 20% of the compounds the data set. [37][38][39] After this, only the modeling set is used to build the models and then the models are validated with the external cross validation technique. [37][38][39] There were 200 the total number of trees constructed and 1 seed in the generation of random numbers for the RF for all generated models.…”

“…[37][38][39] After this, only the modeling set is used to build the models and then the models are validated with the external cross validation technique. [37][38][39] There were 200 the total number of trees constructed and 1 seed in the generation of random numbers for the RF for all generated models.…”

Progress and Impact of Latin American Natural Product Databases

“…In the third VS study, the researchers looked for compounds against Schistosoma mansoni, which causes the chronic parasitic disease Schistosomiasis. From the 1000 alkaloids on SistematX, five compounds were identified with potential multitarget schistosomicidal activity [ 144 ]. In the fourth VS study, 1955 diterpenes on SistematX were employed to search for compounds against SARS-CoV-2.…”

Progress and Impact of Latin American Natural Product Databases

“…In the third VS study, the researchers looked for compounds against Schistosoma mansoni, which causes the chronic parasitic disease Schistosomiasis. From 1000 alkaloids of SistematX, five compounds were identified with potential multitarget schistosomicidal activity [143]. In the fourth VS study, 1955 diterpenes of SistematX were employed to search for compounds against SARS-CoV-2.…”