Characterizing RNA-binding Ligands on Structures, Chemical Information, Binding Affinity and Drug-likeness

ABSTRACT Recent studies suggest RNAs playing essential roles in many cell activities and act as promising drug targets. However, limited development has been achieved in detecting RNA-ligand interactions. To guide the discovery of RNA-binding ligands, it is necessary to characterize them comprehensively. We established a database, RNALID that collects RNA-ligand interactions validated by low-throughput experiment. RNALID contains 358 RNA-ligand interactions. Comparing to other databases, 94.5% of ligands in RNALID are completely or partially novel collections, and 51.78% have novel two-dimensional (2D) structures. The ligand structure analysis indicated that multivalent ligands (MV), ligands binding with cellular mRNA (mRNA), ligands binding with RNA from virus (vRNA) and ligands binding with RNA containing repetitive sequence (rep RNA) are more structurally conserved in both 2D and 3D structures than other ligand types. Binding affinity analysis revealed that interactions between ligands and rep RNA were significantly stronger (two-tailed MW-U test P-value = 0.012) than the interactions between ligands and non-rep RNAs; the interactions between ligands and vRNA were significantly stronger (two-tailed MW-U test P-value = 0.012) than those between ligands and mRNA. Drug-likeness analysis indicated that small molecule (SM) ligands binding with non-rep RNA or vRNA may have higher probability to be drugs than other types of ligands. Comparing ligands in RNALID to FDA-approved drugs and ligands without bioactivity indicated that RNA-binding ligands are different from them in chemical properties, structural properties and drug-likeness. Thus, characterizing the RNA-ligand interactions in RNALID in multiple respects provides new insights into discovering and designing druggable ligands binding with RNA. KEY POINTSWe established a database, RNALID, by collecting RNA-ligand interactions validated by low-throughput experiments, which contains 358 RNA-ligand interactions, and 94.5% of them are completely or partially novel collections.Ligands in RNALID were divided into fourteen types, and were analyzed on chemical properties, spatial properties, binding affinity and drug-likeness. Small molecule (SM) ligands binding with non-repeat RNA or virus RNA were indicated having higher probability to be drugs than other types of ligands.Ligands in RNALID were different from protein-binding ligands and ligands without bioactivity in chemical properties, structural properties and drug-likeness.