Design of dual cyclooxygenase-2 and 5-lipoxygenase inhibitors with iron-chelating properties – molecular docking

Inflammation has an important function in progression of some diseases, such as cancer. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) pathways provides a rational strategy for development of more effective and safer anti-inflammatory drugs. It is assumed that compounds bearing sulfohydroxamic acid chelate catalytic iron inside 5-LOX enzyme and there are only few publications about performed molecular docking studies on these compounds. The main aim of our study was to establish valid and accurate molecular docking platform for future in silico screening and design of promising dual COX-2 and 5-LOX inhibitors with terminal sulfohydroxamic group. GOLD (Genetic Optimisation for Ligand Docking) software v.5.7 was used in order to predict the binding modes and docking poses of previously published dual COX-2 and 5-LOX inhibitors compounds in the active sites of COX-1, COX-2 and 5-LOX enzymes. Crystal structures were downloaded from the PDB website: 5WBE (for COX-1), 1CX2 (for COX-2) and 3O8Y (for 5-LOX). The first step was to investigate binding modes and docking poses of sulfohydroxamic analogues taken from literature, which expressed dual COX-2 and 5-LOX inhibitory activities and to establish correlation between experimentally obtained inhibitory activities and calculated scoring functions (ChemPLP for COX-1 and COX-2 enzymes, ASPFF for 5-LOX enzyme). Nine newly designed sulfohydroxamic analogues were docked into COX-1, COX-2 and 5-LOX enzymes. In the case of COX-2 enzyme, all designed compounds showed the same binding pattern as the co-crystalized ligand, SC-558, while no significant interactions were observed in the COX-1 enzyme. The compounds had lower ChemPLP scores when docked into COX-1 enzyme comparing to COX-2, which indicated good in silico predicted COX-2 selectivity. Obtained ASPFF and docking poses indicate that these compounds are potential 5-LOX chelating inhibitors. In this study, we developed valid molecular docking models to accelerate in silico identification and design of dual COX-2 and 5-LOX inhibitors bearing sulfohydroxamic acids.BOOK OF ABSTRACTS, Paul Ehrlich Euro-PhD Network Virtual Meeting 202