Evaluation of quinoxaline compounds as ligands of a site adjacent to S2 (AS2) of cruzain |
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| Institution: | 1. CONICET-Universidad de Buenos Aires, Instituto de la Química y Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, Argentina;2. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Medicinal, Buenos Aires, Argentina;3. Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIB-INTECH-UNSAM), San Martín, Argentina;4. Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Inorgánica, Analítica y Química-Física, Buenos Aires, Argentina;5. CONICET-Universidad de Buenos Aires, Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE), Buenos Aires, Argentina;1. Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil;2. Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil;3. Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil;1. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Medicinal, Junín 956 PP 1113, Buenos Aires, Argentina;2. CONICET-Universidad de Buenos Aires, Instituto de la Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956 SS 1113, Buenos Aires, Argentina;3. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Orgánica, Junín 956 3er floor, Buenos Aires, Argentina;1. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil;2. Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil;3. Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais 31270-901 Belo Horizonte, MG, Brazil;4. Escola de Farmácia, Universidade Federal de Ouro Preto, 35400-000 Ouro Preto, MG, Brazil;5. Fundação Oswaldo Cruz, Instituto Carlos Chagas, 81350-010 Curitiba, PR, Brazil;6. Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil;7. Faculdade de Medicina, Programa em Ciências da Saúde: Infectologia e Medicina Tropical, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;1. Laboratory of Medicinal Chemistry, Federal University of Alagoas, Alagoas, Brazil;2. Institute of Chemistry and Biotechnology, Federal University of Alagoas, Alagoas, Brazil;3. Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany;1. College of Chemistry, Green Catalysis Center, Zhengzhou University, Zhengzhou 450052, China;2. Tetranov Biopharm, LLC., Zhengzhou 450052, China;3. Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA |
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| Abstract: | The binding of ten quinoxaline compounds (1–10) to a site adjacent to S2 (AS2) of cruzain (CRZ) was evaluated by a protocol that include a first analysis through docking experiments followed by a second analysis using the Molecular Mechanics-Poisson-Boltzmann Surface Area method (MM-PBSA). Through them we demonstrated that quinoxaline compounds bearing substituents of different sizes at positions 3 or 4 of the heterocyclic ring might interact with the AS2, particularly interesting site for drug design. These compounds showed docking scores (ΔGdock) which were similar to those estimated for inhibitors that bind to the enzyme through non-covalent interactions. Nevertheless, the free binding energies (ΔG) values estimated by MM-PBSA indicated that the derivatives 8–10, which bear bulky substituents at position 3 of the heterocycle ring, became detached from the binding site under a dynamic study. Surprisingly, the evaluation of the inhibitory activity of cruzipain (CZ) of some derivatives showed that they increase the enzymatic activity. These results lead us to conclude about the relevance of AS2 as a pocket for compounds binding site, but not necessarily for the design of anti-chagasic compounds. |
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| Keywords: | Cruzain (CRZ) Docking MM-PBSA Quinoxaline compounds Cruzipain (CZ) inhibition assay |
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