PLBを利用した蛋白質モデル構造における医薬分子結合部位の予測 Identification of druggable concavity in homology model by use of PLB index

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Abstract

蛋白質表面における医薬分子結合部位を予測することは、医薬品開発、特にSBDD(Structure-Based Drug Design)において重要なステップである。最近我々は、標的蛋白質において医薬分子が結合する部位をかなり高い確率で予測する手法、PLB法、を開発し、その有用性について報告している。本発表では、PLB法の適用対象を、X線結晶構造だけではなくホモロジー・モデリングで得られるモデル構造にまで拡大できることを示し、創薬研究においてPLB法が非常に実用的な方法になり得ることを述べる。

Identification of the druggable concavity, where druglike molecules are highly inclined to bind, is an important step in structure-based drug design. We previously developed an index named PLB (propensity for ligand binding). The PLB index was proven to be useful in identifying the druggable concavities in the quality X-ray structures of target proteins. Here, we apply the PLB to predicting the druggable concavity in model structures constructed by homology modeling. In this study, we assembled a set of reference proteins that were accurately determined by X-ray analysis in forms of complexes with druglike small molecules. Homology models for the reference proteins were constructed using multiple homologous proteins as templates. The PLB index was then applied to the homology models to predict the druggable concavities. If a template protein in a complex with a druglike small molecule was used, the druggable concavity was predicted well, with a prediction rate of 78%. Interestingly, even when the percent sequence identity between the reference and template proteins was lower than 30, the PLB index could successfully identify the druggable concavity in some cases. This study has demonstrated the practical value of the PLB index in identifying the drugabble concavity in the homology model.

Journal

  • Proceedings of the Symposium on Chemoinformatics

    Proceedings of the Symposium on Chemoinformatics 2007(0), J08-J08, 2007

    Division of Chemical Information and Computer Sciences The Chemical Society of Japan

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