Ligand-based virtual screening, molecular dynamics, and biological evaluation of repurposed drugs as inhibitors of Trypanosoma cruzi proteasome

Abstract

Chagas disease is a well-known Neglected Tropical Disease, mostly endemic in continental Latin America, but that has spread to North America and Europe. Unfortunately, current treatments against such disease are ineffective and produce known and undesirable side effects. To find novel effective drug candidates to treat Chagas disease, we uniquely explore the Trypanosoma cruzi proteasome as a recent biological target and, also, apply drug repurposing through different computational methodologies. For this, we initially applied protein homology modeling to build a robust model of proteasome β4/β5 subunits, since there is no crystallographic structure of this target. Then, we used it on a drug repurposing via a virtual screening campaign starting with more than 8,000 drugs and including the methodologies: ligand-based similarity, toxicity predictions, and molecular docking. Three drugs were selected concerning their favorable interactions at the protein binding site and subsequently submitted to molecular dynamics simulations, which allowed us to elucidate their behavior and compare such theoretical results with experimental ones, obtained in biological assays also described in this paper.

Communicated by Ramaswamy H. Sarma

Keywords:

• Chagas disease
• drug repurposing
• proteasome
• protein homology modeling
• virtual screening
• molecular dynamics

Acknowledgement

Authors acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for fellowships, and Superintendência de Tecnologia da Informação da Universidade de São Paulo by support for the HPC resources.

Author contributions

Conceptualization and design of the study S.Q.G. and C.H.T.P.S; Acquisition, analysis, and interpretation of data S.Q.G., L.B.F., G.M.S. and C.D.L.; writing—original draft preparation S.Q.G. and C.D.L.; writing—review and editing G.M.S and C.H.T.P.S.; supervision S.A. and C.H.T.P.S. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).