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Front Chem. 2019 Aug 6;7:534. doi: 10.3389/fchem.2019.00534. eCollection 2019.

In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2.

Author information

1
Laboratory of Bioactive Compounds Research and Development (LIDeB), Department of Biological Sciences, Exact Sciences College, Universidad Nacional de La Plata, La Plata, Argentina.
2
Departamento de Biodiversidad y Biología Experimental, Facultad de Farmacia y Bioquímica, Facultad de Ciencias Exactas y Naturales, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisico-Química Biológicas (IQUIFIB) "Prof. Alejandro C. Paladini", Universidad de Buenos Aires, Buenos Aires, Argentina.
3
Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo Ugalde", Universidad Nacional de San Martín, CONICET, Buenos Aires, Argentina.

Abstract

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 non-competitive 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.

KEYWORDS:

Plasmodium falciparum; drug repositioning; drug rescue; falcipain-2; malaria; methacycline; odanacatib; virtual screening

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