TY - JOUR
T1 - Profiling the interaction of 1-phenylbenzimidazoles to cyclooxygenases
AU - Gómez-Castro, Carlos Z.
AU - López-Martínez, Margarita
AU - Hernández-Pineda, Jessica
AU - Trujillo-Ferrara, José G.
AU - Padilla-Martínez, Itzia I.
N1 - Publisher Copyright:
© 2019 John Wiley & Sons, Ltd.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - 1-phenylbenzimidazole
KW - cyclooxygenase
KW - docking
KW - enzyme-inhibitor complex
KW - induced fit
KW - interaction profile
KW - ligand-receptor complex
KW - similarity
UR - http://www.scopus.com/inward/record.url?scp=85070306442&partnerID=8YFLogxK
U2 - 10.1002/jmr.2801
DO - 10.1002/jmr.2801
M3 - Artículo
C2 - 31353677
AN - SCOPUS:85070306442
SN - 0952-3499
VL - 32
JO - Journal of Molecular Recognition
JF - Journal of Molecular Recognition
IS - 11
M1 - e2801
ER -