Virtual Screening for the Selection of New Candidates to Trypanosoma cruzi Farnesyl Pyrophosphate Synthase Inhibitors

Journal of the Brazilian Chemical Society

Oliveira, Larissa M.¹ 

[1] Universidade Estadual de Feira de Santana, Feira de Santana, Brazil

关键词: farnesyl pyrophosphate synthase;    molecular docking;    pharmacophore model;    Trypanosoma cruzi;    virtual screening.;   

DOI  :  10.21577/0103-5053.20180135

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

Chagas disease is a tropical parasitic disease that is caused by Trypanosoma cruzi and causes 12,000 deaths per year, mainly in Latin America. The available drugs for treating have severe limitations, including poor efficacy and high toxicity. One way to overcome these limitations is targeting priority molecules with computational tools to direct in vitro assays against validated targets. Farnesyl pyrophosphate synthase (E.C. 2.5.1.10) is an enzyme that participates in the initial stage of sterol biosynthesis, and its inhibition causes damage to membrane integrity, leading to parasite death. With the aim to identify potential inhibitors against this target from T. cruzi, hierarchical virtual screening approaches were performed through a combination of ligand-based pharmacophore models and molecular docking. First, pharmacophore model filtering resulted in 15,154 molecules that had the minimum structural requirements for inhibition (QFIT > 0). These molecules were subsequently submitted to molecular docking routine, which resulted in 11,762 molecules (Grid Score between -232.74 to -0.96 kcal mol-1). The top 30 ranked molecules in these approaches were grouped in self-organizing maps. These analyses showed four promising compounds from natural products that mimic the major interactions present in the substrate/inhibitor, which indicates that these molecules can be assayed by in vitro experiments.

【 授权许可】

CC BY