Do Naturally Modified Nucleotides Contribute to Stabilizing Complexes between Ribosomes and Small Molecules? A Case Study with the Antitumor Drug Homoharringtonine

Abstract

AbstractModified nucleotides are ubiquitous with RNAs, also in contact with drugs that target the ribosome. Whether this represents a stabilization of the drug‐ribosome complex, thus affecting the drug's affinity and possibly also intrinsic efficacy, remains an open question, however. The challenge of answering this question has been taken here with the only human‐ribosome‐targeting small‐molecule currently in clinical use, the antitumor plant alkaloid homoharringtonine (HHT). The approach consisted in dissecting HHT‐nucleotide interaction energies from QM‐MM simulations in explicit water. What emerged is a network of mostly weak interactions of the large, branched HHT with standard nucleotides and a single modified nucleotide, out of the four ones present at PCT's A site. This is unlike the case of the small, compact marine antitumor alkaloid agelastatin A, which displays only a few, albeit strong, interactions with site‐A ribosome nucleotides. This should aid tailoring drugs targeting the ribosome.