IN SILICO COMPARISON OF RHO-KINASE INHIBITORS - PROTEIN DOCKING AFFINITY

Abstract

Purpose : Rho kinase inhibitors (ROCKi) possess pro-regenerative effects in corneal endothelial cells, as reported in ex vivoand in vivo models. There are several classes of commercially available ROCKi, however, only a few have been tested for corneal regenerative purposes. We have simulated protein docking of different ROCKi and compared their affinity for ROCK-1

Methods : Structures of ROCK-1 were obtained from the Protein Data Bank (PDB). Redundant structures were excluded (clustering cutoff of 0.51). Molecular docking was performed with Schrödinger 2018-2 Glide. The receptors were prepared with Protein Preparation Wizard and ligands with tautomeric and protonation states (LigPrep). For docking, extra precision (XP) mode was used.

Results : A set of 23 ROCK structures was found in the PDB, the maximum/minimum resolutions were of 3.4 Å/2.93 Å,. Seven ROCK-I non-redundant structure were selected for the binding assay .. Out of 46 compounds tested (20 isoquinolines, 15 aminofurazan, 6 benzodiazepine, 4 indazoles and 1 amide), 34 presented a significantly higher affinity for ROCK-1, when compared to Y-27632 (p<0.0001). All ROCKi classes presented a stronger mean docking score than Y-27632 (p<0.0001). The isoquinoline class represented 70% of the drugs within the top ten highest docking scores, with 3 compounds presenting a docking score stronger than -12. There were no significant differences among ROCKi other than Y27632.

Conclusions : There are several ROCKi from different classes with high affinity to ROCK. Their potential in endothelial regenerative treatments should be further investigated with in vitro and in vivo experiments.

This is a 2020 ARVO Annual Meeting abstract.

 

Mean Docking Affinity of different ROCKi for ROCK 1 and 2

 

Bar chart comparing docking affinity of different ROCKi for ROCK 1 and 2