| Topological polar surface area (TPSA) |
The surface area of polar atoms |
Higher TPSA typically suggests improved aqueous solubility and interaction with the polar RNA backbone. A balance is needed, as a large TPSA may reduce membrane permeability. |
| Octanol–water partition coefficient (logP) |
A measure of lipophilicity |
A moderate logP is desirable for RNA-targeting ligands. Highly lipophilic compounds may struggle to interact with the negatively charged, hydrophilic RNA backbone, while very hydrophilic compounds may not penetrate cells effectively. |
| Molecular weight |
The sum of the atomic weights of all the atoms in the molecule |
Larger molecules might have better binding potential due to multiple interaction sites, but they might also face difficulty in membrane penetration. |
| Hydrogen bond donors (HBD) and acceptors (HBA) |
Functional groups capable of forming hydrogen bonds |
Hydrogen bond donors and acceptors are crucial for achieving selectivity and stability in RNA–ligand complexes, and they are essential for optimizing the efficacy of RNA-targeting small molecules. |
| Conformational flexibility |
The ability of a ligand to adopt different conformations |
RNA-binding ligands that are flexible may be able to adapt their structure to fit into different RNA target sites. However, flexibility needs to be balanced, as too much flexibility can reduce binding affinity. |
| Planarity |
Aromatic rings present in the ligand |
Aromatic rings can participate in π–π stacking interactions with RNA bases, a key interaction for small molecules targeting RNA. |
