RNA Services

close collaboration • rapid delivery • flexible solutions • deep expertise

What is RNA?

RNA is often thought of as an unstructured linear biomolecule, but it is in fact structurally rich and capable of forming complex 3D architectures such as aptamers, riboswitches, hairpins, and G-Quadruplexes. Whilst even structured RNAs are highly dynamic, they can create well defined ligand binding pockets suitable for selective small molecule modulation.

Clinically validated RNA-binding small molecules are establishing RNA as a powerful new class of drug targets:

  • Ribocil - translational inhibitor binding an FMN riboswitch
  • Risdiplam - FDA approved splicing modulator targeting SMN2 pre-mRNA
  • Zotatifin - translation regulator stabilising eIF4A-RNA complexes

 

Domainex’s Integrated Strategy for Discovering RNA-Binding Small Molecules

Domainex delivers a collaborative, rapid, and highly flexible RNA-focused discovery workflow that combines:

  1. RNA-focused multi-objective virtual screening via Pareto front selection
  2. High‑sensitivity biophysical characterisation using Spectral Shift and Grating-Coupled Interferometry (GCI)

This integrated approach, powered by Domainex’s structural and biophysical expertise, enables confident identification, validation, and mechanistic profiling of RNA-ligand interactions.

 

Computational Virtual Screening for RNA‑Ligand Discovery

 

Ligand-Based Drug Design (LBDD)

Domainex's ligand-based models rapidly triage chemical space to identify fragments and compounds resembling known RNA-binding chemotypes. These approaches leverage key molecular descriptors including:

  • Shape complementarity
  • Electrostatic similarity
  • Pharmacophore similarity
  • Physiochemical properties

This enables rapid exploration of RNA-relevant chemical space and prioritisation of compounds with the highest likelihood of productive RNA interactions.

Structure-Based Drug Design (SBDD)

To complement ligand-based approaches, Domainex deploy advanced structure-based workflows specifically tailored to RNA targets. These incorporate:

  • RNA pocket detection algorithms
  • State-of-the-art RNA-ligand docking
  • AI-driven RNA binding probability models

These approaches can identify and characterise druggable binding sites

Figure 1. Shape and electrostatic model of S-adenosyl methionine (SAM, top) and SAM-VI-RNA binding model (bottom)

Our methods can account for the unique structural features of RNA, including:

  • Conformational flexibility
  • Non-canonical base pairing
  • Distinct electrostatic environments

Together, these approaches provide detailed structural insight to guide RNA-targeted ligand discovery and optimisation.

Hybrid AI‑Enhanced Virtual Screening

Domainex integrates LBDD and SBDD into a unified, AI‑supported pipeline that:

  • Predicts ligand complementarity with high accuracy
  • Prioritises selective vs non‑selective binders
  • Rapidly ranks our proprietary fragment library for RNA-focused hit discovery

This hybrid approach offers speed, adaptability, and high enrichment, enabling rapid project progression.

Biophysical Assays for Measuring RNA–Small Molecule Binding

Spectral Shift: Medium‑Throughput RNA Binding Analysis

Using labelled RNA, Spectral Shift detects blue/red spectral shifts in the emission spectrum of the fluorophore induced by compound binding. 

Strengths of Spectral Shift:

  • Medium‑throughput, fast turnaround
  • Low RNA consumption
  • Highly reproducible, excellent signal‑to‑noise
  • Suitable for both hit identification and affinity (KD) determination
  • Effective for virtual‑screening follow‑up and fragment screening
Spectral Shift - Small molecule binding to the Tte preQ1 riboswitch

Figure 2: Spectral Shift - Small molecule binding to the Tte preQ1 riboswitch

GCI Small molecule binding to the Tte preQ1 riboswitch

Figure 3: GCI Small molecule binding to the Tte preQ1 riboswitch

Advantages for RNA targets:

  • Extremely low RNA consumption
  • High sensitivity to small‑molecule binding
  • Full kinetic parameter determination (kon, koff)
  • Ideal for hit identification, orthogonal validation, and detailed affinity/kinetic analysis

Post hit generation 

Domainex has experience in RNA hit expansion and can apply its direct-to-biology capabilities to significantly shorten the design-make-test cycle and drive RNA drug discovery programs forward at pace.