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

LUCAS N. ALBERCA; SARA R. CHUGURANSKY; CORA L. ÁLVAREZ ; ALAN TALEVI; EMIR SALAS SURDUY

Frontiers in Chemistry

Frontiers Media

Año: 2019

Malaria is among the leading causes of death worldwide. The emergence of Plasmodium falciparum resistant strains with reducedsensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector managementhave 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 identifyingfalcipain-2 inhibitors, and their subsequent application in the virtual screening of DrugBank and Sweetlead libraries. Among fourhits submitted to enzymatic assays, two (odanacatib, an abandoned investigational treatment for osteoporosis and bonemetastasis, 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‐2hemoglobinase activity and on the development of P. falciparum were also studied.