Evaluation of quinoxaline compounds as ligands of a site adjacent to S2 (AS2) of cruzain.
Fabian, L., Martini, M. F., Sarduy, E. S., Estrin, D. A. and Moglioni, A. G.
CONICET-Universidad de Buenos Aires, Instituto de la Quimica y Metabolismo del Farmaco (IQUIMEFA), Buenos Aires, Argentina.
CONICET-Universidad de Buenos Aires, Instituto de la Quimica y Metabolismo del Farmaco (IQUIMEFA), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Catedra de Quimica Medicinal, Buenos Aires, Argentina.
Instituto de Investigaciones Biotecnologicas-Instituto Tecnologico de Chascomus (IIB-INTECH-UNSAM), San Martin, Argentina.
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Quimica Inorganica, Analitica y Quimica-Fisica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Quimica Fisica de los Materiales, Medio Ambiente y Energia (INQUIMAE), Buenos Aires, Argentina. Electronic address: dario.estrin@de.fcen.uba.ar.
CONICET-Universidad de Buenos Aires, Instituto de la Quimica y Metabolismo del Farmaco (IQUIMEFA), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Catedra de Quimica Medicinal, Buenos Aires, Argentina. Electronic address: amoglio@ffyb.uba.ar.
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 (DeltaGdock) which were similar to those estimated for inhibitors that bind to the enzyme through non-covalent interactions. Nevertheless, the free binding energies (DeltaG) 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.
Bioorganic and Medicinal Chemistry Letters 29(16): 2197-2202 (2019)