In silico guided drug repurposing: discovery of new competitive and noncompetitive inhibitors of falcipain-2

ALBERCA LUCAS N ; CHUGURANSKI SARA R ; ALVAREZ CORA LILIA; TALEVI ALAN; SALAS-SARDUY EMIR

Frontiers in Chemistry

Frontiers Media

Lugar: Laussane; Año: 2019

2296-2646

Malaria is among the leading causes of death worldwide. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector management have led to renewed interest in novel therapeutic options.Here, we report the development and validation of an ensemble of ligand-based computational models capable of identifying falcipain-2 inhibitors, and their subsequent application in the virtual screening of DrugBank and Sweetlead libraries. Among four hits submitted to enzymatic assays, two (odanacatib, an abandoned investigational treatment for osteoporosis and bone metastasis, and the antibiotic methacycline) confirmed inhibitory effects on falcipain-2, with Ki of 98.2 nM and 84.4 µM. Interestingly, Methacycline proved to be a noncompetitive inhibitor (α = 1.42) of falcipain-2. The effects of both hits on falcipain-2 hemoglobinase activity and on the development of P. falciparum were also studied.