Ligand Optimization by Improving Shape Complementarity at a Hepatitis C Virus RNA Target

Abstract

Crystal structure analysis revealed key interactions of a 2-amino-benzimidazole viral translation inhibitor that captures an elongated conformation of an RNA switch target in the internal ribosome entry site (IRES) of hepatitis C virus (HCV). Here, we have designed and synthesized quinazoline derivatives with improved shape complementarity at the ligand binding site of the viral RNA target. A spiro-cyclopropyl modification aimed at filling a pocket in the back of the RNA binding site led to a 5-fold increase of ligand affinity while a slightly more voluminous dimethyl substitution at the same position did not improve binding. We demonstrate that precise shape complementarity based solely on hydrophobic interactions contributes significantly to ligand binding even at a hydrophilic RNA target site such as the HCV IRES conformational switch.

Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold

“…We first assessed the 3D shape coverage of the three sublibraries (ortho, meta, para), as shape is known to be important for RNA recognition. [13a,20] Specifically, we calculated principal moments of inertia (PMI), a spatial measurement that describes ligands as rod, disk, sphere or hybrid. [21] First, a low energy ensemble of each ligand was generated via molecular dynamics simulations (MD) utilizing a generalized Born solvation model.…”

A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing

“…We focused our assays on peptide mimics because the structure of free pre-miR21 revealed a highly flexible large apical loop that presents a very challenging target for small molecule chemistry. Outside of the larger apical loop, the pre-mIR21 hairpin appears devoid of unique structural features that would provide binding site for small molecules, as observed for example in other RNAs targeted for drug discovery such as TAR or RRE from HIV, or the Hep C IRES 9, 24, 63 . The relaxed structure of the hairpin suggested to us that ligands with larger interface area, such as peptides, would be required to gain the binding energy required to conformationally constrain the apical loop and compensate the entropic loss associated with loop rigidification.…”

Functional RNA structures throughout the Hepatitis C Virus genome

“…Crystallographic characterization of a benzimidazole-based inhibitor in complex with this region of domain II reveals a dramatic straightening of the bend, presumably inhibiting the ability of domain II to direct the 40S head-tilt [33] (Figure 2C). Structure-based design is being used to develop more drug-like small molecules with a similar mechanism of action [34]. …”