Identification of small-molecule ligands that bind to MiR-21 as potential therapeutics for endometriosis by screening ZINC database and in-vitro assays

Abstract

MicroRNA-21 (miR-21) is an important regulator of cell signaling pathways involved in the pathogenesis of endometriosis. Here, we attempted to discover new ligands of miR-21 pre-element by carrying out stepwise high-throughput virtual screening against a chemical library consisting of over 4 million lead-like compounds. In the procedure, a synthetic strategy that integrated empirical exclusion, molecular docking, druglikeness evaluation, consensus scoring and manual culling was employed to computationally identify seven promising hits from the large compound library, of which four were determined to have moderate or high affinity for miR-21 pre-element (KD range between 3.7 and 109 μM). We also evaluated the putative binding site and predicted interaction mode of pre-element with its identified compound ligands by inversion mutation of the wild-type pre-element to mutant [U11A/A20U], and explored the sequence-specific recognition in pre-element–ligand interactions by generating a background of numerous random RNA decoys. It was revealed that most of identified pre-element binders are positively charged to meet the electrostatic complementarity with the negative electrostatic potential surface of RNA molecule, and the compound selectivity seems related partially to their affinity.