Pharmacophore modeling, QSAR, and docking studies of Indole Derivatives in the Hit-to-Lead Stage for Chagas Disease

LEE, EUN; DE OLIVEIRA, RAMON G.; CRUZ, LUIZA R.; DOS SANTOS, DEBORAH ; DE OLIVEIRA, LUIZ F. ; MOLLO, MARIA C.; KRATZ, JADEL M.; SJO, PETER; MOWBRAY, CHARLES; DIAS, LUIZ C.

Congreso; Brazilian Symposium on Medicinal Chemistry (BrazMedChem) 2022; 2022

As part of a global cooperation for developing new treatments for neglected tropical diseases (NTDs), the Lead Optimization Latin America (LOLA) consortium aims to discover and develop new and safer medicine to treat Chagas disease (CD), which kills 12.000 people per year in Latin America1. For this, a series of substituted indoles was discovered through a phenotypic screening against Trypanosoma cruzi, and a library with more than 200 compounds was prepared in a hit-to-lead campaign. To help understanding the structure-activity relationships (SAR) and protein-ligand interactions, various computational approaches were performed. Representative compounds were selected according to structural and phenotypic features. Herein, we present the pharmacophore and 3D quantitative SAR models of these indole derivatives. In addition, a docking study of frontrunners compounds LOLA702 and LOLA715 was performed against TcCYP51 to predict a putative binding mode of indole derivatives.