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Journal of Computer-Aided Molecular Design

, Volume 32, Issue 5, pp 591–605 | Cite as

Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations

  • Luan Carvalho Martins
  • Pedro Henrique Monteiro Torres
  • Renata Barbosa de Oliveira
  • Pedro Geraldo Pascutti
  • Elio A. Cino
  • Rafaela Salgado Ferreira
Article

Abstract

Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC50 = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure–activity relationship and optimization. Here, the cruzain binding mode of compound 1 was investigated using docking, molecular dynamics (MD) simulations with ab initio derived parameters, ab initio calculations, and MM/PBSA. Two ligand protonation states and four binding poses were evaluated. A careful ligand parameterization method was employed to derive more physically meaningful parameters than those obtained by automated tools. The poses of unprotonated 1 were unstable in MD, showing large conformational changes and diffusing away from the binding site, whereas the protonated form showed higher stability and interaction with negatively charged residues Asp161 and Cys25. MM/PBSA also suggested that these two residues contribute favorably to binding of compound 1. By combining results from MD, ab initio calculations, and MM/PBSA, a binding mode of 1 is proposed. The results also provide insights for further optimization of 1, an interesting lead compound for the development of new cruzain inhibitors.

Keywords

Cruzain inhibitors Molecular dynamics Binding mode prediction Free energy calculations Ligand parameterization MM/PBSA 

Notes

Acknowledgements

The authors would like to thank Brazilian funding agencies Conselho Nacional do Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Fundação de Amparo à Pesquisa do Estado de Minas Gerais and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro. RSF, RBO and PGP hold CNPq research fellowships (Bolsa de Produtividade em Pesquisa). This research was enabled in part by support provided by Compute Canada (http://www.computecanada.ca).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 742 KB)
10822_2018_112_MOESM2_ESM.top (23 kb)
Supplementary material 2 (TOP 23 KB)
10822_2018_112_MOESM3_ESM.top (24 kb)
Supplementary material 3 (TOP 23 KB)

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e ImunologiaUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Laboratório de Química Farmacêutica, Departamento de Produtos Farmacêuticos, Faculdade de FarmáciaUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  3. 3.Programa de Computação CientíficaFundação Oswaldo Cruz – FIOCRUZRio de JaneiroBrazil
  4. 4.Laboratório de Modelagem e Dinâmica Molecular, Instituto de BiofísicaUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil
  5. 5.Departamento de Bioquímica e ImunologiaUniversidade Federal de Minas GeraisBelo HorizonteBrazil

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