First In Silico Screening of Insect Molecules for Identification of Novel Anti-Parasitic Compounds

Abstract

Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma. In silico screenings of compounds for the identification of novel anti-parasitic drug candidates have received considerable attention in recent years, including the screening of natural compounds. For the first time, we investigated molecules from insects, a rather neglected source in drug discovery, in an in silico screening approach to find novel antischistosomal compounds. Based on the Dictionary of Natural Products (DNP), we created a library of 1327 insect compounds suitable for molecular docking. A structure-based virtual screening against the crystal structure of a known druggable target in Schistosoma mansoni, the thioredoxin glutathione reductase (SmTGR), was performed. The top ten compounds predominantly originated from beetles and were predicted to interact particularly with amino acids in the doorstop pocket of SmTGR. For one compound from a jewel beetle, buprestin H, we tested and confirmed antischistosomal activity against adult and juvenile parasites in vitro. At concentrations with anti-parasitic activity, we could also exclude any unspecific cytotoxic activity against human HepG2 cells. This study highlights the potential of insect molecules for the identification of novel antischistosomal compounds. Our library of insect-derived molecules could serve not only as basis for future in silico screenings against additional target proteins of schistosomes, but also of other parasites.

Therapeutic Potential of Natural Products in the Treatment of Schistosomiasis

“…QSAR models aimed at inhibiting SmTGR were applied to three subsets from the ChemBridge library (∼150,000 compounds), which selected 29 compounds for further testing via two HCS platforms based on image analysis of assay plates. Among these, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing the new chemical scaffolds, were found to exert activity against schistosomula and adult worms at low micromolar concentrations, thus constituting promising antischistosomal agents [103]. A combination of computational techniques that included molecular docking studies also allowed for the evaluation of approximately 1000 insect-derived compounds with demonstrated inhibitory activity against SmTGR [103].…”

“…Among these, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing the new chemical scaffolds, were found to exert activity against schistosomula and adult worms at low micromolar concentrations, thus constituting promising antischistosomal agents [103]. A combination of computational techniques that included molecular docking studies also allowed for the evaluation of approximately 1000 insect-derived compounds with demonstrated inhibitory activity against SmTGR [103]. The applied approach included both the creation of a database of molecules derived from insects and the use of the PLIP (protein-ligand interaction profiler) tool for virtual screening and selection of the best candidates to conduct experimental testing.…”

Computer-Assisted Discovery of Salvia fruticosa Compounds With Schistosomicidal Activity

“… 24 To discover new and affordable treatments for schistosomiasis, computer-aided drug design (CADD) approaches have been employed to develop novel schistosomicidal agents. 16 , 25 - 27 …”

Baicalein Attenuates Myocardial Fibrosis via Directly Targeting Phosphoglycerate Mutase 1

“…Recently, natural products have continued to enter clinical trials or to provide leads for compounds that have entered clinical trials, particularly as anticancer and antimicrobial agents [15]. However, the process of developing a new drug can be long, complex, and uncertain [16]. Virtual screening is a rapid, costeffective method, plays an important role in drug discovery processes.…”