In silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulations
Abstract Based on the in vitro trypanocidal efficacy of previously synthesized N-aryl-1,10-phenanthroline-2-amines (Phen1-20) (aryl = R-phenyl, 1- or 2-naphthyl), we explored the potential interactions of these derivatives as ligands of our comparative model of T. cruzi GP63 (TcGP63). This surface m...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-90088-y |
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| author | Priscila Goes Camargo Ramon Borges da Silva Aline Araujo Zuma Simon J. Garden Magaly Girão Albuquerque Carlos Rangel Rodrigues Camilo Henrique da Silva Lima |
| author_facet | Priscila Goes Camargo Ramon Borges da Silva Aline Araujo Zuma Simon J. Garden Magaly Girão Albuquerque Carlos Rangel Rodrigues Camilo Henrique da Silva Lima |
| author_sort | Priscila Goes Camargo |
| collection | DOAJ |
| description | Abstract Based on the in vitro trypanocidal efficacy of previously synthesized N-aryl-1,10-phenanthroline-2-amines (Phen1-20) (aryl = R-phenyl, 1- or 2-naphthyl), we explored the potential interactions of these derivatives as ligands of our comparative model of T. cruzi GP63 (TcGP63). This surface metalloprotease plays a crucial role in parasite adhesion to host cells and aids in cell invasion during T. cruzi infection in Chagas disease. Ligand-protein consensus docking simulations using four GOLD scoring functions revealed that N-(R-phenyl) derivatives (R = CH3, OCH3, CF3, CN, NO2, F, Cl, and Br) presented poses with higher fitness scores than the N-naphthyl ones, with the six para-substituted derivatives (Phen4, p-CH3; Phen7, p-OCH3; Phen10, p-CN; Phen14, p-F; Phen17, p-Cl; and Phen18, p-Br) being more favorable than the ortho or meta ones. Subsequent aqueous molecular dynamics simulation (GROMACS package, CHARMM36 force field, and TIP3P water model) of the ligand-protein complexes for these six top-ranking compounds showed persistent interactions within the TcGP63 active site, primarily through coordination with Zn(II)-cofactor, and H-bonding with catalytic Glu221 and zinc-binding His224. RMSD and RMSF analyses confirmed the stability of these interactions, particularly for compounds with electron-withdrawing groups by inductive effect as R-substituents, such as p-OCH3 (Phen7) and p-CN (Phen10). Binding free energy calculations by the linear interaction energy (LIE) approach corroborated the favorable interactions observed in simulations, highlighting Phen7 and Phen10 as the most promising candidates. This study underscores the potential of N-phenyl-1,10-phenanthroline-2-amines as putative inhibitors targeting the T. cruzi GP63 enzyme. |
| format | Article |
| id | doaj-art-6c50cebdedc24bbd9ae5d08d546b7d80 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-6c50cebdedc24bbd9ae5d08d546b7d802025-08-20T03:10:52ZengNature PortfolioScientific Reports2045-23222025-02-0115111310.1038/s41598-025-90088-yIn silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulationsPriscila Goes Camargo0Ramon Borges da Silva1Aline Araujo Zuma2Simon J. Garden3Magaly Girão Albuquerque4Carlos Rangel Rodrigues5Camilo Henrique da Silva Lima6Laboratório de Modelagem Molecular e QSAR (ModMolQSAR), Departamento de Fármacos e Medicamentos, Faculdade de Farmácia, Universidade Federal do Rio de JaneiroLaboratório Nacional de Biociências Brasileiras, Centro Brasileiro de Pesquisa em Energia e MateriaisLaboratório de Ultraestrutura Celular Hertha Meyer, Centro de Pesquisas em Medicina de Precisão, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de JaneiroDepartamento de Química Orgânica, Programa de Pós-Graduação em Química (PGQu), Instituto de Química, Universidade Federal do Rio de JaneiroDepartamento de Química Orgânica, Programa de Pós-Graduação em Química (PGQu), Instituto de Química, Universidade Federal do Rio de JaneiroLaboratório de Modelagem Molecular e QSAR (ModMolQSAR), Departamento de Fármacos e Medicamentos, Faculdade de Farmácia, Universidade Federal do Rio de JaneiroDepartamento de Química Orgânica, Programa de Pós-Graduação em Química (PGQu), Instituto de Química, Universidade Federal do Rio de JaneiroAbstract Based on the in vitro trypanocidal efficacy of previously synthesized N-aryl-1,10-phenanthroline-2-amines (Phen1-20) (aryl = R-phenyl, 1- or 2-naphthyl), we explored the potential interactions of these derivatives as ligands of our comparative model of T. cruzi GP63 (TcGP63). This surface metalloprotease plays a crucial role in parasite adhesion to host cells and aids in cell invasion during T. cruzi infection in Chagas disease. Ligand-protein consensus docking simulations using four GOLD scoring functions revealed that N-(R-phenyl) derivatives (R = CH3, OCH3, CF3, CN, NO2, F, Cl, and Br) presented poses with higher fitness scores than the N-naphthyl ones, with the six para-substituted derivatives (Phen4, p-CH3; Phen7, p-OCH3; Phen10, p-CN; Phen14, p-F; Phen17, p-Cl; and Phen18, p-Br) being more favorable than the ortho or meta ones. Subsequent aqueous molecular dynamics simulation (GROMACS package, CHARMM36 force field, and TIP3P water model) of the ligand-protein complexes for these six top-ranking compounds showed persistent interactions within the TcGP63 active site, primarily through coordination with Zn(II)-cofactor, and H-bonding with catalytic Glu221 and zinc-binding His224. RMSD and RMSF analyses confirmed the stability of these interactions, particularly for compounds with electron-withdrawing groups by inductive effect as R-substituents, such as p-OCH3 (Phen7) and p-CN (Phen10). Binding free energy calculations by the linear interaction energy (LIE) approach corroborated the favorable interactions observed in simulations, highlighting Phen7 and Phen10 as the most promising candidates. This study underscores the potential of N-phenyl-1,10-phenanthroline-2-amines as putative inhibitors targeting the T. cruzi GP63 enzyme.https://doi.org/10.1038/s41598-025-90088-yNeglected diseasesChagas diseaseTrypanosoma cruziZinc-metalloproteaseZinc-chelating agentsMolecular dynamics |
| spellingShingle | Priscila Goes Camargo Ramon Borges da Silva Aline Araujo Zuma Simon J. Garden Magaly Girão Albuquerque Carlos Rangel Rodrigues Camilo Henrique da Silva Lima In silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulations Scientific Reports Neglected diseases Chagas disease Trypanosoma cruzi Zinc-metalloprotease Zinc-chelating agents Molecular dynamics |
| title | In silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulations |
| title_full | In silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulations |
| title_fullStr | In silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulations |
| title_full_unstemmed | In silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulations |
| title_short | In silico evaluation of N-aryl-1,10-phenanthroline-2-amines as potential inhibitors of T. cruzi GP63 zinc-metalloprotease by docking and molecular dynamics simulations |
| title_sort | in silico evaluation of n aryl 1 10 phenanthroline 2 amines as potential inhibitors of t cruzi gp63 zinc metalloprotease by docking and molecular dynamics simulations |
| topic | Neglected diseases Chagas disease Trypanosoma cruzi Zinc-metalloprotease Zinc-chelating agents Molecular dynamics |
| url | https://doi.org/10.1038/s41598-025-90088-y |
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