Vitamin D receptor exhibits different pharmacodynamic features in tumoral and normal microenvironments: A molecular modeling study

RIBONE, SERGIO R.; FERRONATO, MARIA J.; VITALE, CRISTIAN; FALL, YAGAMARE; CURINO, ALEJANDRO C.; FACCHINETTI, MARIA M.; QUEVEDO, MARIO A.

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2020 vol. 200

0960-0760

he vitamin D receptor (VDR) constitutes a promising therapeutic target for the treatment of cancer.Unfortunately, its natural agonist calcitriol does not have clinical utility due to its potential to induce hypercalcemiceffects at the concentrations required to display antitumoral activity. For this reason, the search fornew calcitriol analogues with adequate therapeutic profiles has been actively pursued by the scientific community.We have previously reported the obtaining and the biological activity evaluation of new calcitriolanalogues by modification of its sidechain, which exhibited relevant antiproliferative and selectivity profilesagainst tumoral and normal cells. In this work we conducted molecular modeling studies (i.e. molecular docking,molecular dynamics, constant pH molecular dynamics (CpHMD) and free energy of binding analysis) to elucidateat an atomistic level the molecular basis related to the potential of the new calcitriol analogues to achieveselectivity between tumor