Distinct NMR Views Leverage New Strategies in Drug Discovery

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  • 薬剤探索の新たな戦略：NMR 独自の視点の活用
  • ヤクザイ タンサク ノ アラタ ナ センリャク : NMR ドクジ ノ シテン ノ カツヨウ

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Abstract

This review provides an overview of the evolution of drug discovery strategies in recent years and the role of Nuclear Magnetic Resonance (NMR) in these strategies. The strategy known as Structure-Based Drug Discovery (SBDD) emerged following the first report on the three-dimensional structure of protein molecules in 1957. This approach involves the artificial design of drug molecules specifically targeting "actively important sites" based on the three-dimensional structure of proteins. SBDD drugs, however, have encountered issues such as side effects and cell habituation. Consequently, a new concept “allosteric molecule exploration” was born. This involves the design of drug molecules that "change the dynamics of the entire protein molecule to selectively alter activity," a concept distinct from the conventional approach of "turning off active sites." It is considered promising for addressing issues like habituation in cancer cells. Additionally, another new strategy called Protein-Protein Interaction (PPI) inhibitor exploration has emerged. As many PPIs are known to be associated with diseases, SBDD and machine learning are combined to explore molecules that inhibit specific interactions between proteins. NMR is a technique that not only facilitates structural determination but also enables an understanding of the mobility of biomacromolecules, providing valuable information for the exploration of allosteric molecules and PPI inhibitors. Various NMR methods exist, and some application examples are presented in this review. Through this review, we aim to convey that drug discovery strategies are transitioning towards exploring drug molecules that affect the dynamics of the entire target protein molecule, including all residues, not just those related to the function of the protein molecules. Both technically and conceptually, NMR is deemed highly suitable for this new strategy.

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