Pharmacophore Virtual Screening Identifies Riboflavin as an Inhibitor of the Schistosome Cathepsin B1 Protease with Antiparasitic Activity

• Published in: ACS omega Vol. 9; no. 23; pp. 25356 - 25369
• Main Authors: Cogo, Ramon M., Pavani, Thaís F. A., Mengarda, Ana C. A., Cajas, Rayssa A., Teixeira, Thainá R., Fukui-Silva, Lucas, Sun, Yujie Uli, Liu, Lawrence J., Amarasinghe, Dilini K., Yoon, Michael C., Santos-Filho, Osvaldo A., de Moraes, Josué, Caffrey, Conor R., G. G. Rando, Daniela
• Format: Journal Article
• Language: English
• Published: American Chemical Society 30.05.2024
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.4c03376

Schistosomiasis is a neglected disease of poverty that affects over 200 million people worldwide and relies on a single drug for therapy. The cathepsin B1 cysteine protease (SmCB1) of Schistosoma mansoni has been investigated as a potential target. Here, a structure-based pharmacophore virtual screening (VS) approach was used on a data set of approved drugs to identify potential antischistosomal agents targeting SmCB1. Pharmacophore (PHP) models underwent validation through receiver operating characteristics curves achieving values >0.8. The data highlighted riboflavin (RBF) as a compound of particular interest. A 1 μs molecular dynamics simulation demonstrated that RBF altered the conformation of SmCB1, causing the protease’s binding site to close around RBF while maintaining the protease’s overall integrity. RBF inhibited the activity of SmCB1 at low micromolar values and killed the parasite in vitro. Finally, in a murine model of S. mansoni infection, oral administration of 100 mg/kg RBF for 7 days significantly decreased worm burdens by ∼20% and had a major impact on intestinal and fecal egg burdens, which were decreased by ∼80%.