Profiling the interaction of 1-phenylbenzimidazoles to cyclooxygenases
Por:
Gomez-Castro, Carlos Z., Lopez-Martinez, Margarita, Hernandez-Pineda, Jessica, Trujillo-Ferrara, Jose G., Padilla-Martinez, Itzia I.
Publicada:
1 nov 2019
Resumen:
In the design of 1-phenylbenzimidazoles as model cyclooxygenase (COX)
inhibitors, docking to a series of crystallographic COX structures was
performed to evaluate their potential for high-affinity binding and to
reproduce the interaction profile of well-known COX inhibitors. The
effect of ligand-specific induced fit on the calculations was also
studied. To quantitatively compare the pattern of interactions of model
compounds to the profile of several cocrystallized COX inhibitors, a
geometric parameter, denominated ligand-receptor contact distance
(LRCD), was developed. The interaction profile of several model
complexes showed similarity to the profile of COX complexes with
inhibitors such as iodosuprofen, iodoindomethacin, diclofenac, and
flurbiprofen. Shaping of high-affinity binding sites upon
ligand-specific induced fit mostly determined both the affinity and the
binding mode of the ligands in the docking calculations. The results
suggest potential of 1-phenylbenzimidazole derivatives as COX inhibitors
on the basis of their predicted affinity and interaction profile to COX
enzymes. The analyses also provided insights into the role of induced
fit in COX enzymes. While inhibitors produce different local structural
changes at the COX ligand binding site, induced fit allows inhibitors in
diverse chemical classes to share characteristic interaction patterns
that ensure key contacts to be achieved. Different interaction patterns
may also be associated with different inhibitory mechanisms.
Filiaciones:
Gomez-Castro, Carlos Z.:
Univ Autonoma Estado Hidalgo, Inst Ciencias Basicas & Ingn, Area Academ Quim, Ciudad Del Conocimiento, Hidalgo, Mexico
Lopez-Martinez, Margarita:
Inst Nacl Perinatol, Lab Farmacol Expt, Ciudad De Mexico, Mexico
Hernandez-Pineda, Jessica:
Inst Nacl Perinatol, Lab Farmacol Expt, Ciudad De Mexico, Mexico
Trujillo-Ferrara, Jose G.:
Inst Politecn Nacl, Escuela Super Med, Dept Farmacol, Secc Estudios Posgrad & Invest, Ciudad De Mexico, Mexico
Padilla-Martinez, Itzia I.:
Inst Politecn Nacl, Unidad Profes Interdisciplinaria Biotecnol, Lab Quim Supramol & Nanociencias, Ave Acueducto S-N, Ciudad De Mexico 07340, Mexico
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